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Morse, Michael Aaron

Overview:

We are studying the use of immune therapies to treat various cancers, including gastrointestinal, breast, and lung cancers and melanoma. These therapies include vaccines based on dendritic cells developed in our laboratory as well as vaccines based on peptides, viral vectors, and DNA plasmids. Our group is also a national leader in the development and use of laboratory assays for demonstrating immunologic responses to cancer vaccines. Finally, we are developing immunotherapies based on adoptive transfer of tumor and viral antigen-specific T cells.

Our current clinical trials include phase I and II studies of immunotherapy for: patients with metastatic malignancies expressing CEA, pancreatic cancer, colorectal cancer, breast cancer, and ovarian cancer, and leukemias following HSCT. My clinical area of expertise is in gastrointestinal oncology, in particular, the treatment of hepatic malignancies, and malignant melanoma.

Key words: dendritic cells, immunotherapy, vaccines, T cells, gastrointestinal oncology, melanoma, hepatoma

Positions:

Professor of Medicine

Medicine, Medical Oncology
School of Medicine

Professor in the Department of Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1990

M.D. — Yale University

Medical Resident, Medicine

University of Washington

Fellow In Hematology Oncology, Medicine

Duke University

Grants:

A Phase I dose escalation and cohort expansion study of ERY974

Administered By
Duke Cancer Institute
AwardedBy
Chugai Pharmaceutical Company, Ltd.
Role
Principal Investigator
Start Date
November 30, 2016
End Date
December 24, 2021

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

A Phase III study of pemborlizumab (MK-3475) vs chemotherapy in microstatilitte instablility - High (MSI-H) or mismatch repair deficienct (dMMR) stage IV colorectal

Administered By
Duke Cancer Institute
AwardedBy
Merck Sharp & Dohme
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

A Study of fafety tolerabolity and clinical activitiy of MEDI4736 and Tremelimumab administered as monotherapy and in combination to subjects with unresectable heptocellular carcinoma

Administered By
Medicine, Medical Oncology
AwardedBy
MedImmune, Inc.
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2020

A Phase I study of Niclosamide in patients with resectable colon cancer.

Administered By
Duke Cancer Institute
AwardedBy
Bayer HealthCare AG
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2020

A pilot study of active immunotherapy with CEA (6D) VRP vaccine (AVX701) in patients with stage III colon cancer.

Administered By
Duke Cancer Institute
AwardedBy
AlphaVax, Inc.
Role
Principal Investigator
Start Date
October 01, 2013
End Date
September 01, 2019

A phase 2B randomized controlled multicenter open-label study of the efficacy and immune responsoe of GVAX pancreas vacc

Administered By
Duke Cancer Institute
AwardedBy
Aduro BioTech
Role
Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2019

A Phase 1/2 open label study of Nivolumab monotherapy or Nivolumab combined with Ipilimumab in subjects with advanced or

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2019

An Open label single arm phase I study of the pahramcokinetics and safety of Carfilzomib in subjects with advanced malig

Administered By
Duke Cancer Institute
AwardedBy
Onyx Pharmaceuticals, Inc
Role
Principal Investigator
Start Date
December 01, 2013
End Date
November 30, 2018

A phase I/2 open label study of Nivolumab manotherapy or Nivolmab combined with ipilmujab in subjects with advanced or m

Administered By
Duke Cancer Institute
AwardedBy
Bristol-Myers Squibb Company
Role
Principal Investigator
Start Date
November 01, 2013
End Date
December 31, 2017

Long term follow up of subject who participated in aduro sponsored protocols

Administered By
Duke Cancer Institute
AwardedBy
Aduro BioTech
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2017

Novel Immune Modulating Cellular Vaccine for Prostate Cancer Immunotherapy

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2013
End Date
September 29, 2017

Targeting the WNT/beta-catenin Pathway in Triple Negative Breast Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 30, 2013
End Date
September 29, 2017

Oncogenic Signaling Networks

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Clinical Investigator
Start Date
September 30, 2012
End Date
September 29, 2017

Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2012
End Date
September 29, 2017

A multicenter rendomized open label phase 3 trial to compare the efficacy and safety of Lenvatinib versus Sorafenib in f

Administered By
Duke Cancer Institute
AwardedBy
Eisai, Inc.
Role
Principal Investigator
Start Date
November 01, 2013
End Date
October 30, 2016

A Phase 3 randomized placebo contolled parellel-group multicenter double blined study to evaluate the efficacy

Administered By
Duke Cancer Institute
AwardedBy
Lexicon Pharmaceuticals
Role
Principal Investigator
Start Date
September 01, 2014
End Date
October 27, 2015

Using Aptamer Coated Nanoparticles Encapsulating Prostate Tumor Antigen Encoding mRNA to Target Dendritic Cells In Vivo

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Collaborator
Start Date
September 01, 2012
End Date
August 31, 2015

Targeting hCG-beta for Breast Cancer Immunotherapy

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Project Leader
Start Date
January 01, 2004
End Date
December 31, 2009

Vaccination with Regulatory T Cell Depletion

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2006
End Date
June 30, 2008

Biomarker Studies for Novel Anti-Cancer Agents

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 28, 2003
End Date
February 29, 2008

Immunotherapy using peptide MHC tetramer isolated Tcells

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 16, 2002
End Date
July 31, 2007

Dendritic Cell Mobilization and Active Immunotherapy

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
February 16, 2001
End Date
January 31, 2007

Planning a Duke Academic Public Private Partnership Program (AP4) Center

Administered By
Duke Cancer Institute
AwardedBy
National Cancer Institute
Role
Collaborator
Start Date
July 20, 2004
End Date
June 30, 2006

Cancer Care Quality Measures: Diagnosis and Treatment of Colorectal Cancer

Administered By
Institutes and Centers
AwardedBy
Agency for Healthcare Research and Quality
Role
Investigator
Start Date
December 01, 2004
End Date
December 31, 2005

Dexasome Based Immunotherapy of Lung Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2001
End Date
February 28, 2004

Immunotherapy with TRICOM Modified Dendritic Cells

AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 19, 2001
End Date
August 31, 2003
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Publications:

Phase I study of pazopanib plus TH-302 in advanced solid tumors.

To define the maximum tolerated dose (MTD), recommended phase II dose (RPTD), and assess safety and tolerability for the combination of pazopanib plus TH-302, an investigational hypoxia-activated prodrug (HAP), in adult patients with advanced solid tumors.This was an open-label, non-randomized, single-center, phase I trial consisting 2 stages. Stage 1 was a standard "3 + 3" dose escalation design to determine safety and the RPTD for TH-302 plus pazopanib combination. Stage 2 was an expanded cohort to better describe the tolerability and toxicity profile at the MTD. Pazopanib was orally dosed at 800 mg daily on days 1-28 for all cohorts. TH-302 was administered intravenously on days 1, 8 and 15 of a 28-day cycle at doses of 340 mg/m(2) (cohort 1) or 480 mg/m(2) (cohort 2). Dose limiting toxicity (DLT) was assessed in the first 28-day cycle. Efficacy was assessed every 2 cycles.Thirty patients were enrolled between December 2011 and September 2013. In the dose escalation stage, 7 patients were enrolled in the 340 mg/m(2) TH-302 cohort and 6 patients in the 480 mg/m(2) TH-302 cohort. Ten patients were evaluable for DLT. DLTs included grade 2 intolerable esophagitis (n = 1) in the 340 mg/m(2) TH-302 cohort, and grade 3 vaginal inflammation (n = 1) and grade 3 neutropenia with grade 3 thrombocytopenia (n = 1, same patient) in the 480 mg/m(2) TH-302 cohort. The 340 mg/m(2) TH-302 cohort was determined to be MTD and RPTD. The most common treatment-related adverse events were hematologic (anemia, neutropenia, and thrombocytopenia), nausea/vomiting, palmar-plantar erythrodysesthesia syndrome, constipation, fatigue, mucositis, anorexia, pain, and hypertension. Partial response (PR) was observed in 10% (n = 3) of patients, stable disease (SD) in 57% (n = 17), and progressive disease (PD) in 23% (n = 7). Due to toxicity, 3 patients were discontinued from study drug prior to first radiographic assessment but were included in these calculations. Disease control ≥6 months was observed in 37% of patients (n = 11).The RPTD for this novel combination is pazopanib 800 mg daily on days 1-28 plus TH-302 340 mg/m(2) on days 1, 8 and 15 of each 28-day cycle. Preliminary activity was seen in treatment-refractory cancers and supports potential value of co-targeting tumor angiogenesis and tumor hypoxia.

Authors
Riedel, RF; Meadows, KL; Lee, PH; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Niedzwiecki, D; Rushing, CN; Arrowood, CC; Hurwitz, HI
MLA Citation
Riedel, RF, Meadows, KL, Lee, PH, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, Niedzwiecki, D, Rushing, CN, Arrowood, CC, and Hurwitz, HI. "Phase I study of pazopanib plus TH-302 in advanced solid tumors." Cancer chemotherapy and pharmacology (February 25, 2017).
PMID
28238078
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Publish Date
2017
DOI
10.1007/s00280-017-3256-2

Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas.

MEDI-565, a bispecific, single-chain antibody targeting human carcinoembryonic antigen on tumor cells and the CD3 epsilon subunit of the human T-cell receptor complex, showed antitumor activity in carcinoembryonic antigen-expressing tumors in murine models.This phase I, multicenter, open-label dose escalation study enrolled adults with gastrointestinal adenocarcinomas. MEDI-565 was given intravenously over 3 hours on days 1 through 5 in 28-day cycles, with 4 single-patient (0.75-20 μg) and 5 standard 3 + 3 escalation (60 μg-3 mg; 1.5-7.5 mg with dexamethasone) cohorts. Primary objective was determining maximum tolerated dose; secondary objectives were evaluating pharmacokinetics, antidrug antibodies, and antitumor activity.Thirty-nine patients were enrolled (mean age, 59 years; 56% male; 72% colorectal cancer). Four patients experienced dose-limiting toxicities (2 at 3 mg; 2 at 7.5 mg + dexamethasone): hypoxia (n = 2), diarrhea, and cytokine release syndrome (CRS). Five patients reported grade 3 treatment-related adverse events: diarrhea, CRS, increased alanine aminotransferase, hypertension (all, n = 1), and hypoxia (n = 2); 6 experienced treatment-related serious adverse events: diarrhea, vomiting, pyrexia, CRS (all, n = 1), and hypoxia (n = 2). MEDI-565 pharmacokinetics was linear and dose-proportional, with fast clearance and short half-life. Nineteen patients (48.7%) had antidrug antibodies; 5 (12.8%) had high titers, 2 with decreased MEDI-565 concentrations. No objective responses occurred; 11 (28%) had stable disease as best response.The maximum tolerated dose of MEDI-565 in this patient population was 5 mg administered over 3 hours on days 1 through 5 every 28 days, with dexamethasone. Pharmacokinetics were linear. No objective responses were observed.

Authors
Pishvaian, M; Morse, MA; McDevitt, J; Norton, JD; Ren, S; Robbie, GJ; Ryan, PC; Soukharev, S; Bao, H; Denlinger, CS
MLA Citation
Pishvaian, M, Morse, MA, McDevitt, J, Norton, JD, Ren, S, Robbie, GJ, Ryan, PC, Soukharev, S, Bao, H, and Denlinger, CS. "Phase 1 Dose Escalation Study of MEDI-565, a Bispecific T-Cell Engager that Targets Human Carcinoembryonic Antigen, in Patients With Advanced Gastrointestinal Adenocarcinomas." Clinical colorectal cancer 15.4 (December 2016): 345-351.
PMID
27591895
Source
epmc
Published In
Clinical colorectal cancer
Volume
15
Issue
4
Publish Date
2016
Start Page
345
End Page
351
DOI
10.1016/j.clcc.2016.07.009

Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma.

High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIMSM registry was established to collect and analyze data for patients treated with HD IL-2 in the current era. This analysis includes 170 patients with mM and 192 patients with mRCC treated between 2005 and 2012 with survival data current as of July 27, 2015. For patients with mM, complete response (CR) was observed in 5 %, partial response (PR) in 10 %, stable disease (SD) in 22 %, and 63 % had progressive disease (PD). The median overall survival (mOS) for these patients was 19.6 months, with a median follow-up of 43.1 months. The mOS was not reached for patients achieving CR or PR, and was 33.4 months for patients with SD. For patients with mRCC, 6 % achieved CR, 9 % had PR, 22 % had SD, and 62 % had PD. The mOS was 41 months, with a median follow-up of 46.6 months. The mOS for patients who had CR and PR was not reached and was 49.6 months for patients with SD. There were no treatment-related deaths among 362 patients. The duration of mOS for patients with mM and mRCC is longer than historically reported. These data support a continued role for IL-2 in the treatment of eligible patients with mM or mRCC and warrant further evaluation of HD IL-2 in combination or sequence with other therapeutic agents.

Authors
Alva, A; Daniels, GA; Wong, MKK; Kaufman, HL; Morse, MA; McDermott, DF; Clark, JI; Agarwala, SS; Miletello, G; Logan, TF; Hauke, RJ; Curti, B; Kirkwood, JM; Gonzalez, R; Amin, A; Fishman, M; Agarwal, N; Lowder, JN; Hua, H; Aung, S; Dutcher, JP
MLA Citation
Alva, A, Daniels, GA, Wong, MKK, Kaufman, HL, Morse, MA, McDermott, DF, Clark, JI, Agarwala, SS, Miletello, G, Logan, TF, Hauke, RJ, Curti, B, Kirkwood, JM, Gonzalez, R, Amin, A, Fishman, M, Agarwal, N, Lowder, JN, Hua, H, Aung, S, and Dutcher, JP. "Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma." Cancer immunology, immunotherapy : CII 65.12 (December 2016): 1533-1544.
PMID
27714434
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
65
Issue
12
Publish Date
2016
Start Page
1533
End Page
1544
DOI
10.1007/s00262-016-1910-x

Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden.

Patients with metastatic disease of the liver can have hyperbilirubinemia due to a number of reasons, including biliary obstruction. The purpose of this study was to analyze patient outcomes after percutaneous biliary drainage (PBD) catheter insertion in patients with extensive hepatic metastatic tumor burden.Out of 746 PBD insertions, 44 patients (24 males, 20 females, mean age 57.4 years, range, 34-80 years) had metastatic malignancy with a hepatic tumor burden of greater than 20% parenchymal volume based on pre-procedure computed tomography (CT) or magnetic resonance imaging (MRI). Laboratory data before and after PBD insertion were compared. Survival and outcomes analysis performed. A subanalysis was performed on patients with CT-demonstrated catheter traversal of tumoral tissue.A PBD catheter was successfully inserted in all patients. The mean serum bilirubin level decreased significantly from 10.9±6.4 mg/dL immediately prior to PBD insertion to 7.1±5.6 mg/dL (P<0.001) within one month post PBD insertion. Four patients (11%) demonstrated normalization of bilirubin levels to less than 1.6 mg/dL. Of the 14 patients with a post-procedure CT or MRI, the PBD catheter traversed a tumor in 11 (79%). One of these patients required a transfusion after the procedure and one had recurrent catheter exchanges due to pericatheter leakage. The 30-day overall survival was 41% with a median survival of 19 days. The percentage decrease in serum bilirubin after PBD insertion and pre-procedure international normalized ratio (INR) were correlated with improved survival (OR =3.7, P=0.010 and OR =4.9, P=0.028 respectively). The PBD-associated major complication rate was 16%.In patients with hyperbilirubinemia and extensive hepatic metastatic disease burden, survival was dismal after PBD catheter insertion. Serum bilirubin level normalization occurred rarely.

Authors
Langman, EL; Suhocki, PV; Hurwitz, HI; Morse, MA; Burbridge, RA; Smith, TP; Kim, CY
MLA Citation
Langman, EL, Suhocki, PV, Hurwitz, HI, Morse, MA, Burbridge, RA, Smith, TP, and Kim, CY. "Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden." Journal of gastrointestinal oncology 7.6 (December 2016): 875-881.
PMID
28078111
Source
epmc
Published In
Journal of Gastrointestinal Oncology
Volume
7
Issue
6
Publish Date
2016
Start Page
875
End Page
881
DOI
10.21037/jgo.2016.06.13

Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.

Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy.In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394.Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9-16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3-35·4) of 78 patients. Grade 3-4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died.Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma.Bristol-Myers Squibb.

Authors
Sharma, P; Callahan, MK; Bono, P; Kim, J; Spiliopoulou, P; Calvo, E; Pillai, RN; Ott, PA; de Braud, F; Morse, M; Le, DT; Jaeger, D; Chan, E; Harbison, C; Lin, C-S; Tschaika, M; Azrilevich, A; Rosenberg, JE
MLA Citation
Sharma, P, Callahan, MK, Bono, P, Kim, J, Spiliopoulou, P, Calvo, E, Pillai, RN, Ott, PA, de Braud, F, Morse, M, Le, DT, Jaeger, D, Chan, E, Harbison, C, Lin, C-S, Tschaika, M, Azrilevich, A, and Rosenberg, JE. "Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial." The Lancet. Oncology 17.11 (November 2016): 1590-1598.
PMID
27733243
Source
epmc
Published In
The Lancet Oncology
Volume
17
Issue
11
Publish Date
2016
Start Page
1590
End Page
1598
DOI
10.1016/s1470-2045(16)30496-x

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM(SM).

This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2).Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin(R) Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM(SM)) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015.Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2.HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients.

Authors
Clark, JI; Wong, MKK; Kaufman, HL; Daniels, GA; Morse, MA; McDermott, DF; Agarwala, SS; Lewis, LD; Stewart, JH; Vaishampayan, U; Curti, B; Gonzalez, R; Lutzky, J; Rudraptna, V; Cranmer, LD; Jeter, JM; Hauke, RJ; Miletello, G; Milhem, MM; Amin, A; Richart, JM; Fishman, M; Hallmeyer, S; Patel, SP; Van Veldhuizen, P; Agarwal, N; Taback, B; Treisman, JS; Ernstoff, MS; Perritt, JC; Hua, H; Rao, TB; Dutcher, JP; Aung, S
MLA Citation
Clark, JI, Wong, MKK, Kaufman, HL, Daniels, GA, Morse, MA, McDermott, DF, Agarwala, SS, Lewis, LD, Stewart, JH, Vaishampayan, U, Curti, B, Gonzalez, R, Lutzky, J, Rudraptna, V, Cranmer, LD, Jeter, JM, Hauke, RJ, Miletello, G, Milhem, MM, Amin, A, Richart, JM, Fishman, M, Hallmeyer, S, Patel, SP, Van Veldhuizen, P, Agarwal, N, Taback, B, Treisman, JS, Ernstoff, MS, Perritt, JC, Hua, H, Rao, TB, Dutcher, JP, and Aung, S. "Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM(SM)." Clinical genitourinary cancer (October 29, 2016).
PMID
27916626
Source
epmc
Published In
Clinical genitourinary cancer
Publish Date
2016
DOI
10.1016/j.clgc.2016.10.008

A phase 1 dose-escalation study of NEO-102 in patients with refractory colon and pancreatic cancer.

NEO-102 is a novel chimeric IgG1 monoclonal antibody which recognizes a variant form of MUC5AC expressed specifically by human pancreatic and colorectal tumors. Preclinical models have demonstrated encouraging signs of anti-tumor activity through antibody-dependent cell-mediated cytotoxicity.This is a phase 1, dose-escalation trial of NEO-102 (Ensituximab) for patients with refractory pancreatic and colorectal cancer. The primary objective was to determine safety and tolerability of escalating doses of NEO-102. Secondary objectives were to assess pharmacokinetics, anti-tumor activity and biologic correlates. Patients whose tumors express NPC-1 antigen were eligible. Dose-escalation was performed in a 3 + 3 design at doses of 1.5, 2, 3 and 4 mg/kg.A total of 19 patients (4 pancreatic and 15 colon cancer) were enrolled at participating institutions in the treatment phase. Most common treatment-related adverse events included anemia, fatigue, fevers, chills and flushing. There was no detectable hemolysis. Of twelve patients evaluable for disease response, the response rate at week 8 included 5 patients with stable disease and 8 patients with progressive disease (PD). Treatment-related grade 3/4 hyperbilirubinemia and anemia were observed at 4 mg/m2. Reversible hypoxia at 3 mg/kg was a dose-limiting toxicity. The maximum tolerated dose was established at 3 mg/kg. Of 74 patients who underwent tissue screening, positive NPC-1 expression was 47 % in colon and 59 % in pancreatic cancer.Treatment with the NEO-102, in this first-in-human study, is well tolerated with a manageable safety profile. A maximum tolerated dose of 3 mg/kg has been established. Toxicity profile is typical for this therapeutic class and allows for combination with conventional cytotoxic therapies.

Authors
Beg, MS; Azad, NS; Patel, SP; Torrealba, J; Mavroukakis, S; Beatson, MA; Wang, XP; Arlen, PM; Morse, MA
MLA Citation
Beg, MS, Azad, NS, Patel, SP, Torrealba, J, Mavroukakis, S, Beatson, MA, Wang, XP, Arlen, PM, and Morse, MA. "A phase 1 dose-escalation study of NEO-102 in patients with refractory colon and pancreatic cancer." Cancer chemotherapy and pharmacology 78.3 (September 2016): 577-584.
PMID
27449137
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
78
Issue
3
Publish Date
2016
Start Page
577
End Page
584
DOI
10.1007/s00280-016-3108-5

Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer.

Division of colorectal cancers (CRCs) into molecular subsets yields important consequences for prognosis and therapeutic response. The microsatellite instability (MSI) immune subgroup, accounting for 15 % of early-stage and 3 % of metastatic CRCs, are a result of deficient cellular DNA mismatch repair (dMMR) mechanisms. dMMR CRCs are notable for greater survivability, yet lack of benefit from fluoropyrimidine-based therapy in early-stage disease as compared to proficient DNA mismatch repair (pMMR) CRCs but are substantially lethal when metastatic. The surging interest in cancer immunotherapy, particularly checkpoint blockade, has further led to a focus on MSI tumors, which are notable for their substantial T cell infiltrate. In this review, we will discuss the biologic underpinnings for the immunogenicity of dMMR CRC and the preclinical development of therapies intended to modulate this immune response. Next, we will discuss the previous and ongoing clinical trials specifically designed to evaluate immunotherapeutic treatment of dMMR CRCs. Building on the success of the early immune checkpoint inhibitor clinical trials for dMMR CRC, combinations with other anti-tumor immunotherapies may provide an even more robust response, thereby, creating an alternative treatment regimen for those who have failed standard therapies or possibly resulting in prophylactic therapies for patients with highly oncogenic hereditary mismatch repair deficiencies.

Authors
Quiroga, D; Lyerly, HK; Morse, MA
MLA Citation
Quiroga, D, Lyerly, HK, and Morse, MA. "Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer." Current treatment options in oncology 17.8 (August 2016): 41-. (Review)
PMID
27315067
Source
epmc
Published In
Current Treatment Options in Oncology
Volume
17
Issue
8
Publish Date
2016
Start Page
41
DOI
10.1007/s11864-016-0414-4

Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.

Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens.The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394.Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis.Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC.Bristol-Myers Squibb.

Authors
Antonia, SJ; López-Martin, JA; Bendell, J; Ott, PA; Taylor, M; Eder, JP; Jäger, D; Pietanza, MC; Le, DT; de Braud, F; Morse, MA; Ascierto, PA; Horn, L; Amin, A; Pillai, RN; Evans, J; Chau, I; Bono, P; Atmaca, A; Sharma, P; Harbison, CT; Lin, C-S; Christensen, O; Calvo, E
MLA Citation
Antonia, SJ, López-Martin, JA, Bendell, J, Ott, PA, Taylor, M, Eder, JP, Jäger, D, Pietanza, MC, Le, DT, de Braud, F, Morse, MA, Ascierto, PA, Horn, L, Amin, A, Pillai, RN, Evans, J, Chau, I, Bono, P, Atmaca, A, Sharma, P, Harbison, CT, Lin, C-S, Christensen, O, and Calvo, E. "Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial." The Lancet. Oncology 17.7 (July 2016): 883-895.
PMID
27269741
Source
epmc
Published In
The Lancet Oncology
Volume
17
Issue
7
Publish Date
2016
Start Page
883
End Page
895
DOI
10.1016/s1470-2045(16)30098-5

Immunotherapy for Resected Pulmonary Metastases.

Micrometastatic disease following pulmonary metastasectomy is an ideal setting to test adjuvant immunotherapy, as the efficacy of immunotherapy in experimental models is greatest with the smallest tumor burdens. Although there is not a standard-of-care adjuvant immunotherapy for resected pulmonary metastases, there have been several studies using cytokines and other immunostimulatory molecules in conjunction with metastasectomies in patients with melanoma, renal cell carcinoma, sarcoma, and colorectal cancer, which have provided preliminary data that such adjuvant therapy is feasible and safe and may be useful in the future, following more rigorous testing, as routine therapy to prevent recurrences.

Authors
Morse, MA
MLA Citation
Morse, MA. "Immunotherapy for Resected Pulmonary Metastases." Thoracic surgery clinics 26.1 (February 2016): 69-78. (Review)
PMID
26611512
Source
epmc
Published In
Thoracic Surgery Clinics
Volume
26
Issue
1
Publish Date
2016
Start Page
69
End Page
78
DOI
10.1016/j.thorsurg.2015.09.009

The Outlook for Immune Checkpoint Targeting Strategies in Colorectal Cancer

Authors
Morse, MA
MLA Citation
Morse, MA. "The Outlook for Immune Checkpoint Targeting Strategies in Colorectal Cancer." Current Colorectal Cancer Reports 12.1 (February 2016): 51-56.
Source
crossref
Published In
Current Colorectal Cancer Reports
Volume
12
Issue
1
Publish Date
2016
Start Page
51
End Page
56
DOI
10.1007/s11888-016-0309-6

X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity.

Inflammatory breast cancer (IBC) is the deadliest, distinct subtype of breast cancer. High expression of epidermal growth factor receptors [EGFR or human epidermal growth factor receptor 2 (HER2)] in IBC tumors has prompted trials of anti-EGFR/HER2 monoclonal antibodies to inhibit oncogenic signaling; however, de novo and acquired therapeutic resistance is common. Another critical function of these antibodies is to mediate antibody-dependent cellular cytotoxicity (ADCC), which enables immune effector cells to engage tumors and deliver granzymes, activating executioner caspases. We hypothesized that high expression of anti-apoptotic molecules in tumors would render them resistant to ADCC. Herein, we demonstrate that the most potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), overexpressed in IBC, drives resistance to ADCC mediated by cetuximab (anti-EGFR) and trastuzumab (anti-HER2). Overexpression of XIAP in parental IBC cell lines enhances resistance to ADCC; conversely, targeted downregulation of XIAP in ADCC-resistant IBC cells renders them sensitive. As hypothesized, this ADCC resistance is in part a result of the ability of XIAP to inhibit caspase activity; however, we also unexpectedly found that resistance was dependent on XIAP-mediated, caspase-independent suppression of reactive oxygen species (ROS) accumulation, which otherwise occurs during ADCC. Transcriptome analysis supported these observations by revealing modulation of genes involved in immunosuppression and oxidative stress response in XIAP-overexpressing, ADCC-resistant cells. We conclude that XIAP is a critical modulator of ADCC responsiveness, operating through both caspase-dependent and -independent mechanisms. These results suggest that strategies targeting the effects of XIAP on caspase activation and ROS suppression have the potential to enhance the activity of monoclonal antibody-based immunotherapy.

Authors
Evans, MK; Sauer, SJ; Nath, S; Robinson, TJ; Morse, MA; Devi, GR
MLA Citation
Evans, MK, Sauer, SJ, Nath, S, Robinson, TJ, Morse, MA, and Devi, GR. "X-linked inhibitor of apoptosis protein mediates tumor cell resistance to antibody-dependent cellular cytotoxicity." Cell death & disease 7 (January 28, 2016): e2073-.
Website
http://hdl.handle.net/10161/12402
PMID
26821068
Source
epmc
Published In
Cell Death and Disease
Volume
7
Publish Date
2016
Start Page
e2073
DOI
10.1038/cddis.2015.412

Durability of responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 (HD IL-2).

Authors
Clark, J; Morse, MA; Wong, MKK; McDermott, DF; Kaufman, H; Daniels, GA; Perritt, JC; Hua, H; Aung, S
MLA Citation
Clark, J, Morse, MA, Wong, MKK, McDermott, DF, Kaufman, H, Daniels, GA, Perritt, JC, Hua, H, and Aung, S. "Durability of responses in patients with metastatic renal cell carcinoma treated with high-dose interleukin-2 (HD IL-2)." January 10, 2016.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
34
Issue
2
Publish Date
2016

Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome.

Studies have suggested increased cancer incidence associated with long-term dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). We evaluated cancer incidence and treatment-related differences in an analysis of DAPT for ACS.The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes trial enrolled 9326 participants with ACS, who received aspirin plus clopidogrel or prasugrel. Median treatment exposure was 15 months. Cancer history and screening procedures were collected. Suspected non-benign neoplasm events were reported and adjudicated. The primary outcome was detection of new, non-benign neoplasm. Factors associated with neoplasm events, the relationship of these events to cardiovascular and bleeding endpoints, and treatment-related differences in neoplasm detection were studied. Among 9240 participants who received ≥1 dose of study drug, 1.8% had a confirmed neoplasm event. The efficacy composite of cardiovascular death, myocardial infarction, or stroke occurred more frequently among those with a neoplasm event vs. those without (18.2 vs. 13.5%) as did Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding (11.2 vs. 1.5%). Screening rates were substantially higher in North America and Western Europe/Scandinavia vs. other regions. Factors most strongly associated with detection of neoplasm events were older age, region, male sex, and current/recent smoking. Among the pre-specified population without a history of neoplasm or previous curative treatment for neoplasm (n = 9105), the incidence of neoplasm events was similar with prasugrel vs. clopidogrel (1.8 vs. 1.7%; HR = 1.04; 95% CI 0.77-1.42; P = 0.79).Neoplasm events were infrequent during long-term DAPT after ACS, were associated with differential cancer-screening practices across regions, and the frequency of neoplasm detection was similar with prasugrel vs. clopidogrel.ClinicalTrials.gov identifier: NCT00699998.

Authors
Roe, MT; Cyr, DD; Eckart, D; Schulte, PJ; Morse, MA; Blackwell, KL; Ready, NE; Zafar, SY; Beaven, AW; Strickler, JH; Onken, JE; Winters, KJ; Houterloot, L; Zamoryakhin, D; Wiviott, SD; White, HD; Prabhakaran, D; Fox, KAA; Armstrong, PW; Ohman, EM
MLA Citation
Roe, MT, Cyr, DD, Eckart, D, Schulte, PJ, Morse, MA, Blackwell, KL, Ready, NE, Zafar, SY, Beaven, AW, Strickler, JH, Onken, JE, Winters, KJ, Houterloot, L, Zamoryakhin, D, Wiviott, SD, White, HD, Prabhakaran, D, Fox, KAA, Armstrong, PW, and Ohman, EM. "Ascertainment, classification, and impact of neoplasm detection during prolonged treatment with dual antiplatelet therapy with prasugrel vs. clopidogrel following acute coronary syndrome." European heart journal 37.4 (January 2016): 412-422.
PMID
26637834
Source
epmc
Published In
European Heart Journal (Elsevier)
Volume
37
Issue
4
Publish Date
2016
Start Page
412
End Page
422
DOI
10.1093/eurheartj/ehv611

A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma.

High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored.The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed.A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death.In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

Authors
Buchbinder, EI; Gunturi, A; Perritt, J; Dutcher, J; Aung, S; Kaufman, HL; Ernstoff, MS; Miletello, GP; Curti, BD; Daniels, GA; Patel, SP; Kirkwood, JM; Hallmeyer, S; Clark, JI; Gonzalez, R; Richart, JM; Lutzky, J; Morse, MA; Sullivan, RJ; McDermott, DF
MLA Citation
Buchbinder, EI, Gunturi, A, Perritt, J, Dutcher, J, Aung, S, Kaufman, HL, Ernstoff, MS, Miletello, GP, Curti, BD, Daniels, GA, Patel, SP, Kirkwood, JM, Hallmeyer, S, Clark, JI, Gonzalez, R, Richart, JM, Lutzky, J, Morse, MA, Sullivan, RJ, and McDermott, DF. "A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma." Journal for immunotherapy of cancer 4 (January 2016): 52-.
PMID
27660706
Source
epmc
Published In
Journal for ImmunoTherapy of Cancer
Volume
4
Publish Date
2016
Start Page
52
DOI
10.1186/s40425-016-0155-8

Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2

Authors
Wong, MKK; Morse, MA; McDermott, DF; Clark, JI; Kaufman, HL; Daniels, GA; Hua, H; Aung, S
MLA Citation
Wong, MKK, Morse, MA, McDermott, DF, Clark, JI, Kaufman, HL, Daniels, GA, Hua, H, and Aung, S. "Overall survival of metastatic melanoma patients treated with HD IL-2 followed by immune checkpoint blockade of the CTLA-4 or the PD-1 pathways: Analysis of data on the current use of HD IL-2." CANCER IMMUNOLOGY RESEARCH 4.1 (January 2016).
Source
wos-lite
Published In
Cancer Immunology Research
Volume
4
Issue
1
Publish Date
2016

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

INTRODUCTION: Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment. METHODS: We devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform. RESULTS: We found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo. CONCLUSIONS: This is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients.

Authors
Ren, XR; Wang, J; Osada, T; Mook, RA; Morse, MA; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Ren, XR, Wang, J, Osada, T, Mook, RA, Morse, MA, Barak, LS, Lyerly, HK, and Chen, W. "Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth." Breast cancer research : BCR 17.1 (December 2015): 528-.
PMID
25778364
Source
epmc
Published In
Breast Cancer Research
Volume
17
Issue
1
Publish Date
2015
Start Page
528

Checkpoint blockade in combination with cancer vaccines.

Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Checkpoint blockade in combination with cancer vaccines." Vaccine 33.51 (December 2015): 7377-7385. (Review)
PMID
26482147
Source
epmc
Published In
Vaccine
Volume
33
Issue
51
Publish Date
2015
Start Page
7377
End Page
7385
DOI
10.1016/j.vaccine.2015.10.057

The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion.

This study aimed to assess the prognostic value of CD4+CD25+ T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy.217 patients participated in the follow-up study. CD4+CD25+ proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4+CD25+ proportion more than 5% and less than or equal to 5% in peripheral T cells.Peripheral CD4+CD25+ T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4+CD25+ proportion of T cells was related with the median overall survival by a shorten of 51 months (p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4+CD25+proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients.Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4+CD25+T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.

Authors
Song, Q-K; Ren, J; Zhou, X-N; Wang, X-L; Song, G-H; Di, L-J; Yu, J; Hobeika, A; Morse, MA; Yuan, Y-H; Yang, H-B; Lyerly, HK
MLA Citation
Song, Q-K, Ren, J, Zhou, X-N, Wang, X-L, Song, G-H, Di, L-J, Yu, J, Hobeika, A, Morse, MA, Yuan, Y-H, Yang, H-B, and Lyerly, HK. "The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion." Oncotarget 6.38 (December 2015): 41350-41359.
PMID
26462021
Source
epmc
Published In
Oncotarget
Volume
6
Issue
38
Publish Date
2015
Start Page
41350
End Page
41359
DOI
10.18632/oncotarget.5534

Durability of responses in patients with metastatic renal cell carcinoma treated with high dose lnterleukin-2 (HD IL-2)

Authors
Clark, JI; Morse, MA; Wong, MKK; Mcdermott, DF; Kaufman, HL; Daniels, GA; Perritt, JC; Hua, H; Aung, S
MLA Citation
Clark, JI, Morse, MA, Wong, MKK, Mcdermott, DF, Kaufman, HL, Daniels, GA, Perritt, JC, Hua, H, and Aung, S. "Durability of responses in patients with metastatic renal cell carcinoma treated with high dose lnterleukin-2 (HD IL-2)." December 2015.
Source
wos-lite
Published In
Bju International
Volume
116
Publish Date
2015
Start Page
6
End Page
6

NIVOLUMAB (NIVO) MONOTHERAPY OR IN COMBINATION WITH IPILIMUMAB (IPI) FOR TREATMENT OF RECURRENT SMALL CELL LUNG CANCER (SCLC)

Authors
Calvo, E; Lopez-Martin, J; Bendell, J; Eder, JP; Taylor, M; Ott, PA; Pietanza, MC; Horn, L; Jaeger, D; de Braud, F; Morse, MA; Ascierto, PA; Le, DT; Amin, A; Evans, J; Simon, JS; Lin, C-S; Christensen, O; Antonia, SJ
MLA Citation
Calvo, E, Lopez-Martin, J, Bendell, J, Eder, JP, Taylor, M, Ott, PA, Pietanza, MC, Horn, L, Jaeger, D, de Braud, F, Morse, MA, Ascierto, PA, Le, DT, Amin, A, Evans, J, Simon, JS, Lin, C-S, Christensen, O, and Antonia, SJ. "NIVOLUMAB (NIVO) MONOTHERAPY OR IN COMBINATION WITH IPILIMUMAB (IPI) FOR TREATMENT OF RECURRENT SMALL CELL LUNG CANCER (SCLC)." Asia-Pacific Journal of Clinical Oncology 11 (November 2015): 118-118.
Source
wos-lite
Published In
Asia-Pacific Journal of Clinical Oncology
Volume
11
Publish Date
2015
Start Page
118
End Page
118

Phase 1/2 study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032

Authors
Antonia, SJ; Bendell, J; Taylor, M; Calvo, E; Jaeger, D; de Braud, F; Ott, PA; Pietanza, MC; Horn, L; Le, DT; Morse, MA; Lopez-Martin, JA; Ascierto, PA; Christensen, O; Grosso, JF; Simon, J; Lin, C; Eder, JP
MLA Citation
Antonia, SJ, Bendell, J, Taylor, M, Calvo, E, Jaeger, D, de Braud, F, Ott, PA, Pietanza, MC, Horn, L, Le, DT, Morse, MA, Lopez-Martin, JA, Ascierto, PA, Christensen, O, Grosso, JF, Simon, J, Lin, C, and Eder, JP. "Phase 1/2 study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032." October 2015.
Source
wos-lite
Published In
Annals of Oncology
Volume
26
Publish Date
2015
Start Page
74
End Page
75

Nivolumab (NIVO) monotherapy or in combination with ipilimumab (IPI) for treatment of recurrent small cell lung cancer (SCLC)

Authors
Calvo, E; Lopez-Martin, JA; Bendell, J; Eder, JP; Taylor, M; Ott, PA; Pietanza, MC; Horn, L; Jaeger, D; De Braud, F; Morse, MA; Ascierto, PA; Le, DT; Amin, A; Evans, J; Simon, J; Lin, CS; Christensen, O; Antonia, SJ
MLA Citation
Calvo, E, Lopez-Martin, JA, Bendell, J, Eder, JP, Taylor, M, Ott, PA, Pietanza, MC, Horn, L, Jaeger, D, De Braud, F, Morse, MA, Ascierto, PA, Le, DT, Amin, A, Evans, J, Simon, J, Lin, CS, Christensen, O, and Antonia, SJ. "Nivolumab (NIVO) monotherapy or in combination with ipilimumab (IPI) for treatment of recurrent small cell lung cancer (SCLC)." September 2015.
Source
wos-lite
Published In
European Journal of Cancer
Volume
51
Publish Date
2015
Start Page
S633
End Page
S633

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.

A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.

Authors
Balint, JP; Gabitzsch, ES; Rice, A; Latchman, Y; Xu, Y; Messerschmidt, GL; Chaudhry, A; Morse, MA; Jones, FR
MLA Citation
Balint, JP, Gabitzsch, ES, Rice, A, Latchman, Y, Xu, Y, Messerschmidt, GL, Chaudhry, A, Morse, MA, and Jones, FR. "Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer." Cancer immunology, immunotherapy : CII 64.8 (August 2015): 977-987.
PMID
25956394
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
8
Publish Date
2015
Start Page
977
End Page
987
DOI
10.1007/s00262-015-1706-4

Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients.

DepoVax™ is an innovative and strongly immunogenic vaccine platform. Survivin is highly expressed in many tumor types and has reported prognostic value. To generate tumor-specific immune response, a novel cancer vaccine was formulated in DepoVax platform (DPX-Survivac) using survivin HLA class I peptides. Safety and immune potency of DPX-Survivac was tested in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients. All the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generating significantly higher magnitude responses. Strong T cell responses were associated with differentiation of naïve T cells into central/effector memory (CM/EM) and late differentiated (LD) polyfunctional antigen-specific CD4+ and CD8+ T cells. This approach enabled rapid de novo activation/expansion of vaccine antigen-specific CD8+ T cells and provided a strong rationale for further testing to determine clinical benefits associated with this immune activation. These data represent vaccine-induced T cell activation in a clinical setting to a self-tumor antigen previously described only in animal models.

Authors
Berinstein, NL; Karkada, M; Oza, AM; Odunsi, K; Villella, JA; Nemunaitis, JJ; Morse, MA; Pejovic, T; Bentley, J; Buyse, M; Nigam, R; Weir, GM; MacDonald, LD; Quinton, T; Rajagopalan, R; Sharp, K; Penwell, A; Sammatur, L; Burzykowski, T; Stanford, MM; Mansour, M
MLA Citation
Berinstein, NL, Karkada, M, Oza, AM, Odunsi, K, Villella, JA, Nemunaitis, JJ, Morse, MA, Pejovic, T, Bentley, J, Buyse, M, Nigam, R, Weir, GM, MacDonald, LD, Quinton, T, Rajagopalan, R, Sharp, K, Penwell, A, Sammatur, L, Burzykowski, T, Stanford, MM, and Mansour, M. "Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients." Oncoimmunology 4.8 (August 2015): e1026529-.
PMID
26405584
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
8
Publish Date
2015
Start Page
e1026529
DOI
10.1080/2162402x.2015.1026529

CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1.

Bispecific T cell-engaging (BiTE) antibodies recruit polyclonal cytotoxic T cells (CTL) to tumors. One such antibody is carcinoembryonic antigen (CEA) BiTE that mediates T cell/tumor interaction by simultaneously binding CD3 expressed by T cells and CEA expressed by tumor cells. A widely operative mechanism for mitigating cytotoxic T cell-mediated killing is the interaction of tumor-expressed PD-L1 with T cell-expressed PD-1, which may be partly reversed by PD-1/PD-L1 blockade. We hypothesized that PD-1/PD-L1 blockade during BiTE-mediated T cell killing would enhance CTL function. Here, we determined the effects of PD-1 and PD-L1 blockade during initial T cell-mediated killing of CEA-expressing human tumor cell lines in vitro, as well as subsequent T cell-mediated killing by T lymphocytes that had participated in tumor cell killing. We observed a rapid upregulation of PD-1 expression and diminished cytolytic function of T cells after they had engaged in CEA BiTE-mediated killing of tumors. T cell cytolytic activity in vitro could be maximized by administration of anti-PD-1 or anti-PD-L1 antibodies alone or in combination if applied prior to a round of T cell killing, but T cell inhibition could not be fully reversed by this blockade once the T cells had killed tumor. In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use.

Authors
Osada, T; Patel, SP; Hammond, SA; Osada, K; Morse, MA; Lyerly, HK
MLA Citation
Osada, T, Patel, SP, Hammond, SA, Osada, K, Morse, MA, and Lyerly, HK. "CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1." Cancer immunology, immunotherapy : CII 64.6 (June 2015): 677-688.
PMID
25742933
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
6
Publish Date
2015
Start Page
677
End Page
688
DOI
10.1007/s00262-015-1671-y

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer

© Springer-Verlag Berlin Heidelberg 2015.A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20Â% (median survival 11Âmonths) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.

Authors
Balint, JP; Gabitzsch, ES; Rice, A; Latchman, Y; Xu, Y; Messerschmidt, GL; Chaudhry, A; Morse, MA; Jones, FR
MLA Citation
Balint, JP, Gabitzsch, ES, Rice, A, Latchman, Y, Xu, Y, Messerschmidt, GL, Chaudhry, A, Morse, MA, and Jones, FR. "Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer." Cancer Immunology, Immunotherapy 64.8 (May 9, 2015): 977-987.
Source
scopus
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
8
Publish Date
2015
Start Page
977
End Page
987
DOI
10.1007/s00262-015-1706-4

Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors.

Most dendritic cell (DC)-based vaccines have loaded the DC with defined antigens, but loading with autologos tumor-derived antigens would generate DCs that activate personalized tumor-specific T-cell responses. We hypothesized that DC matured with an optimized combination of reagents and loaded with tumor-derived antigens using a clinically feasible electroporation strategy would induce potent antitumor immunity. We first studied the effects on DC maturation and antigen presentation of the addition of picibanil (OK432) to a combination of zoledronic acid, tumor necrosis factor-α, and prostaglandin E2. Using DC matured with the optimized combination, we tested 2 clinically feasible sources of autologous antigen for electroloading, total tumor mRNA or total tumor lysate, to determine which stimulated more potent antigen-specific T cells in vitro and activated more potent antitumor immunity in vivo. The combination of tumor necrosis factor-α/prostaglandin E2/zoledronic acid/OK432 generated DC with high expression of maturation markers and antigen-specific T-cell stimulatory function in vitro. Mature DC electroloaded with tumor-derived mRNA [mRNA electroporated dendritic cell (EPDC)] induced greater expansion of antigen-specific T cells in vitro than DC electroloaded with tumor lysate (lysate EPDC). In a therapeutic model of MC38-carcinoembryonic antigen colon cancer-bearing mice, vaccination with mRNA EPDC induced the most efficient anti-carcinoembryonic antigen cellular immune response, which significantly suppressed tumor growth. In conclusion, mature DC electroloaded with tumor-derived mRNA are a potent cancer vaccine, especially useful when specific tumor antigens for vaccination have not been identified, allowing autologous tumor, and if unavailable, allogeneic cell lines to be used as an unbiased source of antigen. Our data support clinical testing of this strategy.

Authors
Osada, T; Nagaoka, K; Takahara, M; Yang, XY; Liu, C-X; Guo, H; Roy Choudhury, K; Hobeika, A; Hartman, Z; Morse, MA; Lyerly, HK
MLA Citation
Osada, T, Nagaoka, K, Takahara, M, Yang, XY, Liu, C-X, Guo, H, Roy Choudhury, K, Hobeika, A, Hartman, Z, Morse, MA, and Lyerly, HK. "Precision cancer immunotherapy: optimizing dendritic cell-based strategies to induce tumor antigen-specific T-cell responses against individual patient tumors." Journal of immunotherapy (Hagerstown, Md. : 1997) 38.4 (May 2015): 155-164.
PMID
25839441
Source
epmc
Published In
Journal of Immunotherapy
Volume
38
Issue
4
Publish Date
2015
Start Page
155
End Page
164
DOI
10.1097/cji.0000000000000075

Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer.

GVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma.Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response.A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm.Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

Authors
Le, DT; Wang-Gillam, A; Picozzi, V; Greten, TF; Crocenzi, T; Springett, G; Morse, M; Zeh, H; Cohen, D; Fine, RL; Onners, B; Uram, JN; Laheru, DA; Lutz, ER; Solt, S; Murphy, AL; Skoble, J; Lemmens, E; Grous, J; Dubensky, T; Brockstedt, DG; Jaffee, EM
MLA Citation
Le, DT, Wang-Gillam, A, Picozzi, V, Greten, TF, Crocenzi, T, Springett, G, Morse, M, Zeh, H, Cohen, D, Fine, RL, Onners, B, Uram, JN, Laheru, DA, Lutz, ER, Solt, S, Murphy, AL, Skoble, J, Lemmens, E, Grous, J, Dubensky, T, Brockstedt, DG, and Jaffee, EM. "Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 33.12 (April 2015): 1325-1333.
PMID
25584002
Source
epmc
Published In
Journal of Clinical Oncology
Volume
33
Issue
12
Publish Date
2015
Start Page
1325
End Page
1333
DOI
10.1200/jco.2014.57.4244

High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the targeted therapy era: Extension of OS benefits beyond complete response (CR) and partial response (PR).

Authors
Aung, S; Morse, MA; Wong, MKK; Kaufman, H; Daniels, GA; McDermott, DF
MLA Citation
Aung, S, Morse, MA, Wong, MKK, Kaufman, H, Daniels, GA, and McDermott, DF. "High dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the targeted therapy era: Extension of OS benefits beyond complete response (CR) and partial response (PR)." March 1, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
7
Publish Date
2015

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment.We devised an image-based screening platform using membrane localized HER3-YFP to identify small molecules that promote HER3 internalization and degradation. In vitro and in vivo tumor models were used to characterize the signaling effects of perhexiline, an anti-anginal drug, identified by the screening platform.We found perhexiline, an anti-anginal drug, selectively internalized HER3, decreased HER3 expression, and subsequently inhibited signaling downstream of HER3. Consistent with these results, perhexiline inhibited breast cancer cell proliferation in vitro and tumor growth in vivo.This is the first demonstration that HER3 can be targeted with small molecules by eliminating it from the cell membrane. The novel approach used here led to the discovery that perhexiline ablates HER3 expression, and offers an opportunity to identify HER3 ablation modulators as innovative therapeutics to improve survival in breast cancer patients.

Authors
Ren, X-R; Wang, J; Osada, T; Mook, RA; Morse, MA; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Ren, X-R, Wang, J, Osada, T, Mook, RA, Morse, MA, Barak, LS, Lyerly, HK, and Chen, W. "Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth." Breast cancer research : BCR 17 (February 15, 2015): 20-.
PMID
25849870
Source
epmc
Published In
Breast Cancer Research
Volume
17
Publish Date
2015
Start Page
20
DOI
10.1186/s13058-015-0528-9

A multicenter randomized phase II study of NPC-1C (N) in combination with gemcitabine (G) and nab-paclitaxel (A) versus G and A alone in patients with metastatic or locally advanced pancreatic cancer (PC) previously treated with folfirinox (F)

Authors
Duffy, AG; Beg, MS; Greten, TF; Beatson, MA; Mavroukakis, S; Patel, SP; Morse, MA; Arlen, PM
MLA Citation
Duffy, AG, Beg, MS, Greten, TF, Beatson, MA, Mavroukakis, S, Patel, SP, Morse, MA, and Arlen, PM. "A multicenter randomized phase II study of NPC-1C (N) in combination with gemcitabine (G) and nab-paclitaxel (A) versus G and A alone in patients with metastatic or locally advanced pancreatic cancer (PC) previously treated with folfirinox (F)." January 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
3
Publish Date
2015

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

Authors
Wolin, EM; Jarzab, B; Eriksson, B; Walter, T; Toumpanakis, C; Morse, MA; Tomassetti, P; Weber, MM; Fogelman, DR; Ramage, J; Poon, D; Gadbaw, B; Li, J; Pasieka, JL; Mahamat, A; Swahn, F; Newell-Price, J; Mansoor, W; Öberg, K
MLA Citation
Wolin, EM, Jarzab, B, Eriksson, B, Walter, T, Toumpanakis, C, Morse, MA, Tomassetti, P, Weber, MM, Fogelman, DR, Ramage, J, Poon, D, Gadbaw, B, Li, J, Pasieka, JL, Mahamat, A, Swahn, F, Newell-Price, J, Mansoor, W, and Öberg, K. "Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues." Drug design, development and therapy 9 (January 2015): 5075-5086.
PMID
26366058
Source
epmc
Published In
Drug Design, Development and Therapy
Volume
9
Publish Date
2015
Start Page
5075
End Page
5086
DOI
10.2147/dddt.s84177

A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions.

Severe infusion reactions (SIRs) at rates of 5% or less are known side effects of biological agents, including mAbs such as cetuximab. There are currently no prospectively validated risk factors to aid physicians in identifying patients who may be at risk of experiencing an SIR following administration of any of these drugs. A retrospective analysis of 545 banked serum or plasma samples from cancer patients participating in clinical trials of cetuximab was designed to evaluate whether the presence of pretreatment IgE antibodies against cetuximab, as determined by a commercially available assay system, is associated with SIRs during the initial cetuximab infusion. Patients with a positive test indicating the presence of pretreatment antibodies had a higher risk of experiencing an SIR; however, at the prespecified cutoff utilized in this analysis, the test has a relatively low-positive predictive value (0.577 [0.369-0.766]) and a negative predictive value of 0.961 (0.912-0.987) in an unselected patient population. Data collected in this large retrospective validation study support prior observations of an association between the presence of pretreatment IgE antibodies cross-reactive with cetuximab and SIRs. Further analysis of the test's ability to predict patients at risk of an SIR would be required before this assay could be used reliably in this patient population.

Authors
Maier, S; Chung, CH; Morse, M; Platts-Mills, T; Townes, L; Mukhopadhyay, P; Bhagavatheeswaran, P; Racenberg, J; Trifan, OC
MLA Citation
Maier, S, Chung, CH, Morse, M, Platts-Mills, T, Townes, L, Mukhopadhyay, P, Bhagavatheeswaran, P, Racenberg, J, and Trifan, OC. "A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions." Cancer medicine 4.1 (January 2015): 36-42.
PMID
25296628
Source
epmc
Published In
Cancer Medicine
Volume
4
Issue
1
Publish Date
2015
Start Page
36
End Page
42
DOI
10.1002/cam4.333

Extension of survival in patients with metastatic renal cell carcinoma (mRCC) treated with high dose interleukin-2 (HD IL-2) immunotherapy in the post 2006 targeted therapy era

Authors
Clark, JI; Wong, MK; Daniels, GA; Kaufman, HL; McDermott, DF; Morse, MA; Aung, S
MLA Citation
Clark, JI, Wong, MK, Daniels, GA, Kaufman, HL, McDermott, DF, Morse, MA, and Aung, S. "Extension of survival in patients with metastatic renal cell carcinoma (mRCC) treated with high dose interleukin-2 (HD IL-2) immunotherapy in the post 2006 targeted therapy era." October 2014.
Source
wos-lite
Published In
Bju International
Volume
114
Publish Date
2014
Start Page
5
End Page
5

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.

To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational new drugs 32.4 (August 2014): 700-709.
PMID
24711126
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma.

Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established.A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy.With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021).Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.

Authors
Jiang, BS; Beasley, GM; Speicher, PJ; Mosca, PJ; Morse, MA; Hanks, B; Salama, A; Tyler, DS
MLA Citation
Jiang, BS, Beasley, GM, Speicher, PJ, Mosca, PJ, Morse, MA, Hanks, B, Salama, A, and Tyler, DS. "Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma." Annals of surgical oncology 21.8 (August 2014): 2525-2531.
PMID
24700302
Source
epmc
Published In
Annals of Surgical Oncology
Volume
21
Issue
8
Publish Date
2014
Start Page
2525
End Page
2531
DOI
10.1245/s10434-014-3671-0

Immunotherapeutic treatment of metastatic colorectal cancer using ETBX-011

Authors
Gabitzsch, ES; Morse, MA; Lyerly, HK; Balint, J; Jones, F
MLA Citation
Gabitzsch, ES, Morse, MA, Lyerly, HK, Balint, J, and Jones, F. "Immunotherapeutic treatment of metastatic colorectal cancer using ETBX-011." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Molecular profiling of bile duct and gallbladder cancer to identify different therapeutic options.

Authors
Holcombe, RF; Xiu, J; Gatalica, Z; Morse, MA
MLA Citation
Holcombe, RF, Xiu, J, Gatalica, Z, and Morse, MA. "Molecular profiling of bile duct and gallbladder cancer to identify different therapeutic options." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Authors
Turaga, K; Levine, E; Barone, R; Sticca, R; Petrelli, N; Lambert, L; Nash, G; Morse, M; Adbel-Misih, R; Alexander, HR; Attiyeh, F; Bartlett, D; Bastidas, A; Blazer, T; Chu, Q; Chung, K; Dominguez-Parra, L; Espat, NJ; Foster, J; Fournier, K; Garcia, R; Goodman, M; Hanna, N; Harrison, L; Hoefer, R; Holtzman, M; Kane, J; Labow, D; Li, B; Lowy, A; Mansfield, P; Ong, E; Pameijer, C; Pingpank, J; Quinones, M; Royal, R; Salti, G; Sardi, A; Shen, P; Skitzki, J; Spellman, J; Stewart, J; Esquivel, J
MLA Citation
Turaga, K, Levine, E, Barone, R, Sticca, R, Petrelli, N, Lambert, L, Nash, G, Morse, M, Adbel-Misih, R, Alexander, HR, Attiyeh, F, Bartlett, D, Bastidas, A, Blazer, T, Chu, Q, Chung, K, Dominguez-Parra, L, Espat, NJ, Foster, J, Fournier, K, Garcia, R, Goodman, M, Hanna, N, Harrison, L, Hoefer, R, Holtzman, M, Kane, J, Labow, D, Li, B, Lowy, A, Mansfield, P, Ong, E, Pameijer, C, Pingpank, J, Quinones, M, Royal, R, Salti, G, Sardi, A, Shen, P, Skitzki, J, Spellman, J, Stewart, J, and Esquivel, J. "Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States." Annals of surgical oncology 21.5 (May 2014): 1501-1505.
PMID
23793364
Source
epmc
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1501
End Page
1505
DOI
10.1245/s10434-013-3061-z

Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src act expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (January 1, 2014): 330-339.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors

Purpose: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1-14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC. © 2014 Springer Science+Business Media.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational New Drugs 32.4 (January 1, 2014): 700-709.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma

Purpose. Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established. Methods. A prospective, single-institution database of 243 patients with in-transit melanoma (1995-2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher's exact test was used to determine if there was a difference in number of complete responders after immunotherapy. Results. With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021). Conclusions. Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment. © 2014 Society of Surgical Oncology.

Authors
Jiang, BS; Beasley, GM; Speicher, PJ; Mosca, PJ; Morse, MA; Hanks, B; Salama, A; Tyler, DS
MLA Citation
Jiang, BS, Beasley, GM, Speicher, PJ, Mosca, PJ, Morse, MA, Hanks, B, Salama, A, and Tyler, DS. "Immunotherapy following regional chemotherapy treatment of advanced extremity melanoma." Annals of Surgical Oncology 21.8 (January 1, 2014): 2525-2531.
Source
scopus
Published In
Annals of Surgical Oncology
Volume
21
Issue
8
Publish Date
2014
Start Page
2525
End Page
2531
DOI
10.1245/s10434-014-3671-0

Implementation of an Interleukin-2 National Registry: an opportunity to improve cancer outcomes.

Cancer registries have proven valuable with respect to validating therapeutic safety and drug efficacy, uncovering real-world implementation practices, and their evolution over time. Modern cancer therapeutics are approved as single agents oftentimes compared to the least active approved standard agent in randomized trials. However, the burgeoning diversity and number of drugs introduces a complexity that quickly outstrips the knowledge provided by these pivotal trials. This gap in information is particularly relevant when survival is the primary therapeutic endpoint. In addition, the inherent complexity of the immune response will make registries a particularly important tool in expeditiously understanding solid tumor immunotherapy and patient outcomes.

Authors
Wong, MK; Kaufman, HL; Daniels, GA; McDermott, DF; Aung, S; Lowder, JN; Morse, MA
MLA Citation
Wong, MK, Kaufman, HL, Daniels, GA, McDermott, DF, Aung, S, Lowder, JN, and Morse, MA. "Implementation of an Interleukin-2 National Registry: an opportunity to improve cancer outcomes." Journal for immunotherapy of cancer 2 (January 2014): 20-.
PMID
25031835
Source
epmc
Published In
Journal for ImmunoTherapy of Cancer
Volume
2
Publish Date
2014
Start Page
20
DOI
10.1186/2051-1426-2-20

Designing effective vaccines for colorectal cancer.

Achieving long-term control of colorectal cancers with therapeutic vaccines that generate potent anti-tumor T cell and antibody responses has been a goal for more than two decades. To date, clinical trials of these vaccines have demonstrated induction of immune responses, but clinical benefit has been limited. Improved vector delivery systems with enhanced immunostimulatory properties, decreased immunogenicity against vector and improved antigen presentation are some of the key features of modern tumor vaccines. Furthermore, an improved understanding of the various immunosuppressive factors in the tumor microenvironment and regional lymph nodes, coupled with a burgeoning ability to impair inhibitory immune synapses, highlights a growing opportunity to induce beneficial antigen-specific responses against tumor. The combination of improved antigenic delivery systems, coupled with therapeutic immune activation, represents state-of-the-art colorectal vaccine design concepts with the goal of augmenting immune responses against tumor and improving clinical outcomes.

Authors
Patel, SP; Osada, T; Lyerly, HK; Morse, MA
MLA Citation
Patel, SP, Osada, T, Lyerly, HK, and Morse, MA. "Designing effective vaccines for colorectal cancer." Immunotherapy 6.8 (January 2014): 913-926.
PMID
25313570
Source
epmc
Published In
Immunotherapy
Volume
6
Issue
8
Publish Date
2014
Start Page
913
End Page
926
DOI
10.2217/imt.14.61

The Use of Registries to Improve Cancer Treatment: A National Database for Patients Treated with Interleukin-2 (IL-2).

Registries evaluating un-randomized patients have provided valuable information with respect to a therapy's utility, treatment practices, and evolution over time. While immunotherapy for cancer has been around for more than three decades, data collection in the form of a registry has not been undertaken. The authors believe that establishing a registry to study HD IL-2 immunotherapy, which has been the only systemic therapy producing long term unmaintained remissions for advanced kidney cancer and melanoma for over 20 years, will be an important resource in understanding the impact of immunotherapy with HD IL-2 in a rapidly changing therapeutic environment. Optimizing administration and improving selection of appropriate patients likely to benefit from HD IL-2 immunotherapy are two of many benefits to be derived from this endeavor.

Authors
Kaufman, HL; Wong, MK; Daniels, GA; McDermott, DF; Aung, S; Lowder, JN; Morse, MA
MLA Citation
Kaufman, HL, Wong, MK, Daniels, GA, McDermott, DF, Aung, S, Lowder, JN, and Morse, MA. "The Use of Registries to Improve Cancer Treatment: A National Database for Patients Treated with Interleukin-2 (IL-2)." Journal of personalized medicine 4.1 (January 2014): 52-64.
PMID
25562142
Source
epmc
Published In
Journal of Personalized Medicine
Volume
4
Issue
1
Publish Date
2014
Start Page
52
End Page
64
DOI
10.3390/jpm4010052

Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States

Background: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. Methods: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. Results: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. Conclusions: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow. © 2013 Society of Surgical Oncology.

Authors
Turaga, K; Levine, E; Barone, R; Sticca, R; Petrelli, N; Lambert, L; Nash, G; Morse, M; Adbel-Misih, R; Alexander, HR; Attiyeh, F; Bartlett, D; Bastidas, A; Blazer, T; Chu, Q; Chung, K; Dominguez-Parra, L; Espat, NJ; Foster, J; Fournier, K; Garcia, R; Goodman, M; Hanna, N; Harrison, L; Hoefer, R; Holtzman, M; Kane, J; Labow, D; Li, B; Lowy, A; Mansfield, P; Ong, E; Pameijer, C; Pingpank, J; Quinones, M; Royal, R; Salti, G; Sardi, A; Shen, P; Skitzki, J; Spellman, J; Stewart, J; Esquivel, J
MLA Citation
Turaga, K, Levine, E, Barone, R, Sticca, R, Petrelli, N, Lambert, L, Nash, G, Morse, M, Adbel-Misih, R, Alexander, HR, Attiyeh, F, Bartlett, D, Bastidas, A, Blazer, T, Chu, Q, Chung, K, Dominguez-Parra, L, Espat, NJ, Foster, J, Fournier, K, Garcia, R, Goodman, M, Hanna, N, Harrison, L, Hoefer, R, Holtzman, M, Kane, J, Labow, D, Li, B, Lowy, A, Mansfield, P, Ong, E, Pameijer, C, Pingpank, J, Quinones, M, Royal, R, Salti, G, Sardi, A, Shen, P, Skitzki, J, Spellman, J, Stewart, J, and Esquivel, J. "Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States." Annals of Surgical Oncology 21.5 (2014): 1501-1505.
Source
scival
Published In
Annals of Surgical Oncology
Volume
21
Issue
5
Publish Date
2014
Start Page
1501
End Page
1505
DOI
10.1245/s10434-013-3061-z

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer

OBJECTIVE:: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND:: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS:: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS:: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS:: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. © 2013 Lippincott Williams and Wilkins.

Authors
Morse, MA; Niedzwiecki, D; Marshall, JL; Garrett, C; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, AC; Osada, T; Onaitis, M; Clary, BM; Hsu, D; Devi, GR; Bulusu, A; Annechiarico, RP; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Niedzwiecki, D, Marshall, JL, Garrett, C, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, AC, Osada, T, Onaitis, M, Clary, BM, Hsu, D, Devi, GR, Bulusu, A, Annechiarico, RP, Chadaram, V, Clay, TM, and Lyerly, HK. "A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer." Annals of Surgery 258.6 (December 1, 2013): 879-886.
Source
scopus
Published In
Annals of Surgery
Volume
258
Issue
6
Publish Date
2013
Start Page
879
End Page
886
DOI
10.1097/SLA.0b013e318292919e

Modulation of immune system inhibitory checkpoints in colorectal cancer

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress. © Springer Science+Business Media New York 2013.

Authors
Patel, SP; Osada, T; Osada, K; Hurwitz, H; Lyerly, HK; Morse, MA
MLA Citation
Patel, SP, Osada, T, Osada, K, Hurwitz, H, Lyerly, HK, and Morse, MA. "Modulation of immune system inhibitory checkpoints in colorectal cancer." Current Colorectal Cancer Reports 9.4 (December 1, 2013): 391-397.
Source
scopus
Published In
Current Colorectal Cancer Reports
Volume
9
Issue
4
Publish Date
2013
Start Page
391
End Page
397
DOI
10.1007/s11888-013-0184-3

A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer.

OBJECTIVE: To determine whether 1 of 2 vaccines based on dendritic cells (DCs) and poxvectors encoding CEA (carcinoembryonic antigen) and MUC1 (PANVAC) would lengthen survival in patients with resected metastases of colorectal cancer (CRC). BACKGROUND: Recurrences after complete resections of metastatic CRC remain frequent. Immune responses to CRC are associated with fewer recurrences, suggesting a role for cancer vaccines as adjuvant therapy. Both DCs and poxvectors are potent stimulators of immune responses against cancer antigens. METHODS: Patients, disease-free after CRC metastasectomy and perioperative chemotherapy (n = 74), were randomized to injections of autologous DCs modified with PANVAC (DC/PANVAC) or PANVAC with per injection GM-CSF (granulocyte-macrophage colony-stimulating factor). Endpoints were recurrence-free survival overall survival, and rate of CEA-specific immune responses. Clinical outcome was compared with that of an unvaccinated, contemporary group of patients who had undergone CRC metastasectomy, received similar perioperative therapy, and would have otherwise been eligible for the study. RESULTS: Recurrence-free survival at 2 years was similar (47% and 55% for DC/PANVAC and PANVAC/GM-CSF, respectively) (χ P = 0.48). At a median follow-up of 35.7 months, there were 2 of 37 deaths in the DC/PANVAC arm and 5 of 37 deaths in the PANVAC/GM-CSF arm. The rate and magnitude of T-cell responses against CEA was statistically similar between study arms. As a group, vaccinated patients had superior survival compared with the contemporary unvaccinated group. CONCLUSIONS: Both DC and poxvector vaccines have similar activity. Survival was longer for vaccinated patients than for a contemporary unvaccinated group, suggesting that a randomized trial of poxvector vaccinations compared with standard follow-up after metastasectomy is warranted. (NCT00103142).

Authors
Morse, MA; Niedzwiecki, D; Marshall, JL; Garrett, C; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, AC; Osada, T; Onaitis, M; Clary, BM; Hsu, D; Devi, GR; Bulusu, A; Annechiarico, RP; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Niedzwiecki, D, Marshall, JL, Garrett, C, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, AC, Osada, T, Onaitis, M, Clary, BM, Hsu, D, Devi, GR, Bulusu, A, Annechiarico, RP, Chadaram, V, Clay, TM, and Lyerly, HK. "A randomized phase II study of immunization with dendritic cells modified with poxvectors encoding CEA and MUC1 compared with the same poxvectors plus GM-CSF for resected metastatic colorectal cancer." Ann Surg 258.6 (December 2013): 879-886.
PMID
23657083
Source
pubmed
Published In
Annals of Surgery
Volume
258
Issue
6
Publish Date
2013
Start Page
879
End Page
886
DOI
10.1097/SLA.0b013e318292919e

Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302.

Authors
Meadows, KL; Lee, PH; Riedel, RF; Morse, MA; Uronis, HE; Blobe, GC; George, DJ; Crawford, J; Hurwitz, HI
MLA Citation
Meadows, KL, Lee, PH, Riedel, RF, Morse, MA, Uronis, HE, Blobe, GC, George, DJ, Crawford, J, and Hurwitz, HI. "Abstract C61: Phase I Study of pazopanib in combination with the investigational hypoxia-targeted drug TH-302." Molecular Cancer Therapeutics 12.11_Supplement (November 1, 2013): C61-C61.
Source
crossref
Published In
Molecular cancer therapeutics
Volume
12
Issue
11_Supplement
Publish Date
2013
Start Page
C61
End Page
C61
DOI
10.1158/1535-7163.TARG-13-C61

Autoantibody biomarkers identified by proteomics methods distinguish ovarian cancer from non-ovarian cancer with various CA-125 levels.

PURPOSE: CA-125 has been a valuable marker for detecting ovarian cancer, however, it is not sensitive enough to detect early-stage disease and not specific to ovarian cancer. The purpose of our study was to identify autoantibody markers that are specific to ovarian cancer regardless of CA-125 levels. METHODS: Top-down and iTRAQ quantitative proteomics methods were used to identify high-frequency autoantibodies in ovarian cancer. Protein microarrays comprising the recombinant autoantigens were screened using serum samples from various stages of ovarian cancer with diverse levels of CA-125 as well as benign and healthy controls. ROC curve and dot blot analyses were performed to validate the sensitivity and specificity of the autoantibody markers. RESULTS: The proteomics methodologies identified more than 60 potential high-frequency autoantibodies in ovarian cancer. Individual serum samples from ovarian cancer stages I-IV compared to control samples that were screened on a microarray containing native recombinant autoantigens revealed a panel of stage I high-frequency autoantibodies. Preliminary ROC curve and dot blot analyses performed with the ovarian cancer samples showed higher specificity and sensitivity as compared to CA-125. Three autoantibody markers exhibited higher specificity in various stages of ovarian cancer with low and normal CA-125 levels. CONCLUSIONS: Proteomics technologies are suitable for the identification of protein biomarkers and also the identification of autoantibody biomarkers when combined with protein microarray screening. Using native recombinant autoantigen arrays to screen autoantibody markers, it is possible to identify markers with higher sensitivity and specificity than CA-125 that are relevant to early detection of ovarian cancer.

Authors
Karabudak, AA; Hafner, J; Shetty, V; Chen, S; Secord, AA; Morse, MA; Philip, R
MLA Citation
Karabudak, AA, Hafner, J, Shetty, V, Chen, S, Secord, AA, Morse, MA, and Philip, R. "Autoantibody biomarkers identified by proteomics methods distinguish ovarian cancer from non-ovarian cancer with various CA-125 levels." J Cancer Res Clin Oncol 139.10 (October 2013): 1757-1770.
PMID
23999876
Source
pubmed
Published In
Journal of Cancer Research and Clinical Oncology
Volume
139
Issue
10
Publish Date
2013
Start Page
1757
End Page
1770
DOI
10.1007/s00432-013-1501-6

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

Authors
Hanks, BA; Holtzhausen, A; Evans, KS; Jamieson, R; Gimpel, P; Campbell, OM; Hector-Greene, M; Sun, L; Tewari, A; George, A; Starr, M; Nixon, A; Augustine, C; Beasley, G; Tyler, DS; Osada, T; Morse, MA; Ling, L; Lyerly, HK; Blobe, GC
MLA Citation
Hanks, BA, Holtzhausen, A, Evans, KS, Jamieson, R, Gimpel, P, Campbell, OM, Hector-Greene, M, Sun, L, Tewari, A, George, A, Starr, M, Nixon, A, Augustine, C, Beasley, G, Tyler, DS, Osada, T, Morse, MA, Ling, L, Lyerly, HK, and Blobe, GC. "Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment." J Clin Invest 123.9 (September 2013): 3925-3940.
Website
http://hdl.handle.net/10161/13297
PMID
23925295
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
9
Publish Date
2013
Start Page
3925
End Page
3940
DOI
10.1172/JCI65745

Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients.

First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity.

Authors
Morse, MA; Chaudhry, A; Gabitzsch, ES; Hobeika, AC; Osada, T; Clay, TM; Amalfitano, A; Burnett, BK; Devi, GR; Hsu, DS; Xu, Y; Balcaitis, S; Dua, R; Nguyen, S; Balint, JP; Jones, FR; Lyerly, HK
MLA Citation
Morse, MA, Chaudhry, A, Gabitzsch, ES, Hobeika, AC, Osada, T, Clay, TM, Amalfitano, A, Burnett, BK, Devi, GR, Hsu, DS, Xu, Y, Balcaitis, S, Dua, R, Nguyen, S, Balint, JP, Jones, FR, and Lyerly, HK. "Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients." Cancer Immunol Immunother 62.8 (August 2013): 1293-1301.
PMID
23624851
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
8
Publish Date
2013
Start Page
1293
End Page
1301
DOI
10.1007/s00262-013-1400-3

Anti-tumor activity of a novel monoclonal antibody, NPC-1C, optimized for recognition of tumor antigen MUC5AC variant in preclinical models.

PURPOSE: NPC-1C is a chimeric immunoglobulin IgG1 developed from antigen tested in the Hollinshead tumor vaccine trials that recognizes an immunogenic MUC5AC-related tumor-associated antigen. In this article, we describe the pre-clinical characterization of this antibody that is currently being tested in human clinical trials. EXPERIMENTAL DESIGN: The specificity of NPC-1C for pancreatic and colorectal cancer cell lines was tested by flow cytometry assays and immunohistochemical staining. Antibody-dependent cell cytotoxicity was measured using a tumor cell line lysis assay. Anti-tumor efficacy and biodistribution were assessed in nude mice bearing human pancreatic tumor xenografts. RESULTS: Human tumor cell binding measured by flow cytometry ranged from 52 to 94 % of cells stained positive with NPC-1C in three colorectal and one pancreatic cell lines, while IHC demonstrated staining of 43 % of colon cancers and 48 % of pancreatic cancer tissues, with little or no cross-reactivity of NPC-1C with normal colon or pancreas tissues. In vitro NPC-1C-mediated tumor cell killing occurred in a median of 44.5 % of four colorectal and three pancreatic tumor cell lines. In vivo anti-tumor efficacy in a human pancreatic CFPAC-1 tumor xenograft model was demonstrated with a twofold to threefold reduction in tumor growth in the NPC-1C-treated mice compared to saline and human IgG controls. Pharmacodynamic studies indicate NPC-1C localizes in antigen-positive tumors and has minimal uptake in normal mouse tissues. CONCLUSIONS: NPC-1C, a chimeric monoclonal antibody that reacts with a MUC5AC-related antigen expressed by pancreatic and colorectal tumor tissues, has promising preclinical activity in pancreatic and colorectal adenocarcinoma.

Authors
Patel, SP; Bristol, A; Saric, O; Wang, XP; Dubeykovskiy, A; Arlen, PM; Morse, MA
MLA Citation
Patel, SP, Bristol, A, Saric, O, Wang, XP, Dubeykovskiy, A, Arlen, PM, and Morse, MA. "Anti-tumor activity of a novel monoclonal antibody, NPC-1C, optimized for recognition of tumor antigen MUC5AC variant in preclinical models." Cancer Immunol Immunother 62.6 (June 2013): 1011-1019.
PMID
23591984
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
1011
End Page
1019
DOI
10.1007/s00262-013-1420-z

A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT-510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT-510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Thirty-four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment-related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D-dimer, von Willebrand factor, placental growth factor, and stromal-derived factor 1 in response to treatment with the combination of bevacizumab and ABT-510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful.

Authors
Uronis, HE; Cushman, SM; Bendell, JC; Blobe, GC; Morse, MA; Nixon, AB; Dellinger, A; Starr, MD; Li, H; Meadows, K; Gockerman, J; Pang, H; Hurwitz, HI
MLA Citation
Uronis, HE, Cushman, SM, Bendell, JC, Blobe, GC, Morse, MA, Nixon, AB, Dellinger, A, Starr, MD, Li, H, Meadows, K, Gockerman, J, Pang, H, and Hurwitz, HI. "A phase I study of ABT-510 plus bevacizumab in advanced solid tumors." Cancer Med 2.3 (June 2013): 316-324.
Website
http://hdl.handle.net/10161/11086
PMID
23930208
Source
pubmed
Published In
Cancer Medicine
Volume
2
Issue
3
Publish Date
2013
Start Page
316
End Page
324
DOI
10.1002/cam4.65

Abstract LB-164: Treatment of advanced stage colorectal cancer with ETBX-011 immunotherapeutic.

Authors
Gabitzsch, ES; Morse, MA; Lyerly, HK; Jones, F
MLA Citation
Gabitzsch, ES, Morse, MA, Lyerly, HK, and Jones, F. "Abstract LB-164: Treatment of advanced stage colorectal cancer with ETBX-011 immunotherapeutic." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
LB-164
End Page
LB-164
DOI
10.1158/1538-7445.AM2013-LB-164

Abstract LB-161: A phase I safety study of NPC-1C, a novel, therapeutic antibody to treat pancreas and colorectal cancers.

Authors
Patel, SP; Morse, MA; Diaz, LA; Azad, NS; Haley, S; Arlen, PM
MLA Citation
Patel, SP, Morse, MA, Diaz, LA, Azad, NS, Haley, S, and Arlen, PM. "Abstract LB-161: A phase I safety study of NPC-1C, a novel, therapeutic antibody to treat pancreas and colorectal cancers." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
LB-161
End Page
LB-161
DOI
10.1158/1538-7445.AM2013-LB-161

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer

Authors
Aggarwal, C; Meropol, NJ; Punt, CJ; Iannotti, N; Saidman, BH; Sabbath, KD; Gabrail, NY; Picus, J; Morse, MA; Mitchell, E; Miller, MC; Cohen, SJ
MLA Citation
Aggarwal, C, Meropol, NJ, Punt, CJ, Iannotti, N, Saidman, BH, Sabbath, KD, Gabrail, NY, Picus, J, Morse, MA, Mitchell, E, Miller, MC, and Cohen, SJ. "Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer." ANNALS OF ONCOLOGY 24.2 (February 2013): 420-428.
PMID
23028040
Source
wos-lite
Published In
Annals of Oncology
Volume
24
Issue
2
Publish Date
2013
Start Page
420
End Page
428
DOI
10.1093/annonc/mds336

Abstract A29: An Ad5 [E1-, E2b-] platform carrying the TAA CEA(6D) induces CEA directed CMI responses in patients with advanced CEA-expressing colorectal cancer in a phase I/II clinical trial..

Authors
Morse, MA; Gabitzsch, ES; Xu, Y; Rajesh, D; Nguyen, S; Balcaitis, S; Balint, JP; Jones, F
MLA Citation
Morse, MA, Gabitzsch, ES, Xu, Y, Rajesh, D, Nguyen, S, Balcaitis, S, Balint, JP, and Jones, F. "Abstract A29: An Ad5 [E1-, E2b-] platform carrying the TAA CEA(6D) induces CEA directed CMI responses in patients with advanced CEA-expressing colorectal cancer in a phase I/II clinical trial." Cancer Research 73.1 Supplement (January 1, 2013): A29-A29.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
1 Supplement
Publish Date
2013
Start Page
A29
End Page
A29
DOI
10.1158/1538-7445.TUMIMM2012-A29

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism.

X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K (d) > 1 μM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment.

Authors
Allensworth, JL; Sauer, SJ; Lyerly, HK; Morse, MA; Devi, GR
MLA Citation
Allensworth, JL, Sauer, SJ, Lyerly, HK, Morse, MA, and Devi, GR. "Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism." Breast Cancer Res Treat 137.2 (January 2013): 359-371.
Website
http://hdl.handle.net/10161/12454
PMID
23225169
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
137
Issue
2
Publish Date
2013
Start Page
359
End Page
371
DOI
10.1007/s10549-012-2352-6

Immunologic targeting of FOXP3 in inflammatory breast cancer cells.

The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2-overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.

Authors
Nair, S; Aldrich, AJ; McDonnell, E; Cheng, Q; Aggarwal, A; Patel, P; Williams, MM; Boczkowski, D; Lyerly, HK; Morse, MA; Devi, GR
MLA Citation
Nair, S, Aldrich, AJ, McDonnell, E, Cheng, Q, Aggarwal, A, Patel, P, Williams, MM, Boczkowski, D, Lyerly, HK, Morse, MA, and Devi, GR. "Immunologic targeting of FOXP3 in inflammatory breast cancer cells." PLoS One 8.1 (2013): e53150-.
PMID
23341929
Source
pubmed
Published In
PloS one
Volume
8
Issue
1
Publish Date
2013
Start Page
e53150
DOI
10.1371/journal.pone.0053150

A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas.

BACKGROUND: Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. METHODS: Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m(2) BID on days 1-14, and oxaliplatin 130 mg/m(2) with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. RESULTS: Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. CONCLUSIONS: Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

Authors
Uronis, HE; Bendell, JC; Altomare, I; Blobe, GC; Hsu, SD; Morse, MA; Pang, H; Zafar, SY; Conkling, P; Favaro, J; Arrowood, CC; Cushman, SM; Meadows, KL; Brady, JC; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Bendell, JC, Altomare, I, Blobe, GC, Hsu, SD, Morse, MA, Pang, H, Zafar, SY, Conkling, P, Favaro, J, Arrowood, CC, Cushman, SM, Meadows, KL, Brady, JC, Nixon, AB, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas." Oncologist 18.3 (2013): 271-272.
PMID
23485624
Source
pubmed
Published In
The oncologist
Volume
18
Issue
3
Publish Date
2013
Start Page
271
End Page
272
DOI
10.1634/theoncologist.2012-0404

Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion.

Authors
Hamilton, E; Blackwell, K; Hobeika, AC; Clay, TM; Broadwater, G; Ren, XR; Chen, W; Castro, H; Lehmann, F; Spector, N; Wei, J; Osada, T; Lyerly, HK; Morse, MA
MLA Citation
Hamilton, E, Blackwell, K, Hobeika, AC, Clay, TM, Broadwater, G, Ren, XR, Chen, W, Castro, H, Lehmann, F, Spector, N, Wei, J, Osada, T, Lyerly, HK, and Morse, MA. "Correction: phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion." J Transl Med 11 (2013): 82-.
PMID
23536971
Source
pubmed
Published In
Journal of Translational Medicine
Volume
11
Publish Date
2013
Start Page
82
DOI
10.1186/1479-5876-11-82

Biomarkers and correlative endpoints for immunotherapy trials.

Immunotherapies for lung cancer are reaching phase III clinical trial, but the ultimate success likely will depend on developing biomarkers to guide development and choosing patient populations most likely to benefit. Because the immune response to cancer involves multiple cell types and cytokines, some spatially and temporally separated, it is likely that multiple biomarkers will be required to fully characterize efficacy of the vaccine and predict eventual benefit. Peripheral blood markers of response, such as the ELISPOT assay and cytokine flow cytometry analyses of peripheral blood mononuclear cells following immunotherapy, remain the standard approach, but it is increasingly important to obtain tissue to study the immune response at the site of the tumor. Earlier clinical endpoints such as response rate and progression-free survival do not correlate with overall survival demonstrated for some immunotherapies, suggesting the need to develop other intermediary clinical endpoints. Insofar as all these biomarkers and surrogate endpoints are relevant in multiple malignancies, it may be possible to extrapolate findings to immunotherapy of lung cancer.

Authors
Morse, MA; Osada, T; Hobeika, A; Patel, S; Lyerly, HK
MLA Citation
Morse, MA, Osada, T, Hobeika, A, Patel, S, and Lyerly, HK. "Biomarkers and correlative endpoints for immunotherapy trials." Am Soc Clin Oncol Educ Book (2013). (Review)
PMID
23714525
Source
pubmed
Published In
American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting
Publish Date
2013
DOI
10.1200/EdBook_AM.2013.33.e287

Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients

First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Morse, MA; Chaudhry, A; Gabitzsch, ES; Hobeika, AC; Osada, T; Clay, TM; Amalfitano, A; Burnett, BK; Devi, GR; Hsu, DS; Xu, Y; Balcaitis, S; Dua, R; Nguyen, S; Jr, JPB; Jones, FR; Lyerly, HK
MLA Citation
Morse, MA, Chaudhry, A, Gabitzsch, ES, Hobeika, AC, Osada, T, Clay, TM, Amalfitano, A, Burnett, BK, Devi, GR, Hsu, DS, Xu, Y, Balcaitis, S, Dua, R, Nguyen, S, Jr, JPB, Jones, FR, and Lyerly, HK. "Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients." Cancer Immunology, Immunotherapy 62.8 (2013): 1293-1301.
Source
scival
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
8
Publish Date
2013
Start Page
1293
End Page
1301
DOI
10.1007/s00262-013-1400-3

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

X-linked inhibitor of apoptosis protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAIL-sensitive SUM149 (triple-negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149- and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (K d > 1 μM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. By demonstrating that Birinapant primes cancer cells for death in an IAP-dependent manner, these findings support the development of Smac mimetics for IBC treatment. © 2012 Springer Science+Business Media New York.

Authors
Allensworth, JL; Sauer, SJ; Lyerly, HK; Morse, MA; Devi, GR
MLA Citation
Allensworth, JL, Sauer, SJ, Lyerly, HK, Morse, MA, and Devi, GR. "Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism." Breast Cancer Research and Treatment 137.2 (2013): 359-371.
Source
scival
Published In
Breast Cancer Research and Treatment
Volume
137
Issue
2
Publish Date
2013
Start Page
359
End Page
371
DOI
10.1007/s10549-012-2352-6

Modulation of Immune System Inhibitory Checkpoints in Colorectal Cancer

T cell infiltration of colorectal cancer is associated with improved clinical outcome, underlining the importance of the immune system in cancer control; however, immune checkpoints, including the inhibitory T cell molecules CTLA-4 and PD-1 that temper the native immune response, mitigating autoimmunity, are coopted by tumors to facilitate escape from immune surveillance. Blockade of CTLA-4 and PD-1 and its ligand PD-L1, expressed by many tumors, have shown impressive activity in melanoma, renal cell carcinoma, and lung cancer. Immune checkpoint inhibition has been less well studied in colorectal cancer, but preclinical and clinical investigations are in progress. © 2013 Springer Science+Business Media New York.

Authors
Patel, SP; Osada, T; Osada, K; Hurwitz, H; Lyerly, HK; Morse, MA
MLA Citation
Patel, SP, Osada, T, Osada, K, Hurwitz, H, Lyerly, HK, and Morse, MA. "Modulation of Immune System Inhibitory Checkpoints in Colorectal Cancer." Current Colorectal Cancer Reports (2013): 1-7.
Source
scival
Published In
Current Colorectal Cancer Reports
Publish Date
2013
Start Page
1
End Page
7
DOI
10.1007/s11888-013-0184-3

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs (2013): 1-10.
PMID
24173967
Source
scopus
Published In
Investigational New Drugs
Publish Date
2013
Start Page
1
End Page
10

Autoantibody biomarkers identified by proteomics methods distinguish ovarian cancer from non-ovarian cancer with various CA-125 levels

Purpose: CA-125 has been a valuable marker for detecting ovarian cancer, however, it is not sensitive enough to detect early-stage disease and not specific to ovarian cancer. The purpose of our study was to identify autoantibody markers that are specific to ovarian cancer regardless of CA-125 levels. Methods: Top-down and iTRAQ quantitative proteomics methods were used to identify high-frequency autoantibodies in ovarian cancer. Protein microarrays comprising the recombinant autoantigens were screened using serum samples from various stages of ovarian cancer with diverse levels of CA-125 as well as benign and healthy controls. ROC curve and dot blot analyses were performed to validate the sensitivity and specificity of the autoantibody markers. Results: The proteomics methodologies identified more than 60 potential high-frequency autoantibodies in ovarian cancer. Individual serum samples from ovarian cancer stages I-IV compared to control samples that were screened on a microarray containing native recombinant autoantigens revealed a panel of stage I high-frequency autoantibodies. Preliminary ROC curve and dot blot analyses performed with the ovarian cancer samples showed higher specificity and sensitivity as compared to CA-125. Three autoantibody markers exhibited higher specificity in various stages of ovarian cancer with low and normal CA-125 levels. Conclusions: Proteomics technologies are suitable for the identification of protein biomarkers and also the identification of autoantibody biomarkers when combined with protein microarray screening. Using native recombinant autoantigen arrays to screen autoantibody markers, it is possible to identify markers with higher sensitivity and specificity than CA-125 that are relevant to early detection of ovarian cancer. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Karabudak, AA; Hafner, J; Shetty, V; Chen, S; Secord, AA; Morse, MA; Philip, R
MLA Citation
Karabudak, AA, Hafner, J, Shetty, V, Chen, S, Secord, AA, Morse, MA, and Philip, R. "Autoantibody biomarkers identified by proteomics methods distinguish ovarian cancer from non-ovarian cancer with various CA-125 levels." Journal of Cancer Research and Clinical Oncology 139.10 (2013): 1757-1770.
Source
scival
Published In
Journal of Cancer Research and Clinical Oncology
Volume
139
Issue
10
Publish Date
2013
Start Page
1757
End Page
1770
DOI
10.1007/s00432-013-1501-6

Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects.

We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted.

Authors
Osada, T; Berglund, P; Morse, MA; Hubby, B; Lewis, W; Niedzwiecki, D; Yang, XY; Hobeika, A; Burnett, B; Devi, GR; Clay, TM; Smith, J; Kim Lyerly, H
MLA Citation
Osada, T, Berglund, P, Morse, MA, Hubby, B, Lewis, W, Niedzwiecki, D, Yang, XY, Hobeika, A, Burnett, B, Devi, GR, Clay, TM, Smith, J, and Kim Lyerly, H. "Co-delivery of antigen and IL-12 by Venezuelan equine encephalitis virus replicon particles enhances antigen-specific immune responses and antitumor effects." Cancer Immunol Immunother 61.11 (November 2012): 1941-1951.
PMID
22488274
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
61
Issue
11
Publish Date
2012
Start Page
1941
End Page
1951
DOI
10.1007/s00262-012-1248-y

Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines.

BACKGROUND: Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5-FU), in both hepatic tumor cells and stromal cells. METHODS: Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. RESULTS: Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC(50): 5.3 μM in LX2; 32.7 μM in HepG2; Sorafenib IC(50): 11.8 μM in LX2; 9.9 μM in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48-72 hr) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic, leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity, possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. CONCLUSIONS: ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC).

Authors
Rangwala, F; Williams, KP; Smith, GR; Thomas, Z; Allensworth, JL; Lyerly, HK; Diehl, AM; Morse, MA; Devi, GR
MLA Citation
Rangwala, F, Williams, KP, Smith, GR, Thomas, Z, Allensworth, JL, Lyerly, HK, Diehl, AM, Morse, MA, and Devi, GR. "Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines. (Published online)" BMC Cancer 12 (September 10, 2012): 402-.
PMID
22963400
Source
pubmed
Published In
BMC Cancer
Volume
12
Publish Date
2012
Start Page
402
DOI
10.1186/1471-2407-12-402

Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma.

BACKGROUND: Embolizing branches of the hepatic artery lengthens survival for patients with unresectable hepatocellular carcinoma (HCC), but the benefit of combining chemotherapy with the embolizing particles remains controversial. METHODS: A retrospective review was undertaken of sequential patients with advanced HCC undergoing embolization in the past 10 years at 2 neighboring institutions and with 2 years of follow-up data. TACE was generally performed with doxorubicin plus mitomycin C. RESULTS: One hundred twenty-four patients were included; 77 received TACE and 47 received TAE. On multivariable analysis stratified by institution, type of embolization and CLIP score significantly predicted PFS and time to progression (TTP), whereas CLIP score and AFP independently predicted overall survival (OS). TACE significantly prolonged PFS and TTP (P = .0004 and P = .001, respectively), but not OS (P = .83). CONCLUSIONS: The addition of chemotherapy to TAE prolongs PFS and TTP. Future efforts should focus on adjunctive therapies after the embolization to increase survival.

Authors
Morse, MA; Hanks, BA; Suhocki, P; Doan, PL; Liu, EA; Frost, P; Bernard, SA; Tsai, A; Moore, DT; O'Neil, BH
MLA Citation
Morse, MA, Hanks, BA, Suhocki, P, Doan, PL, Liu, EA, Frost, P, Bernard, SA, Tsai, A, Moore, DT, and O'Neil, BH. "Improved time to progression for transarterial chemoembolization compared with transarterial embolization for patients with unresectable hepatocellular carcinoma." Clin Colorectal Cancer 11.3 (September 2012): 185-190.
PMID
22280845
Source
pubmed
Published In
Clinical colorectal cancer
Volume
11
Issue
3
Publish Date
2012
Start Page
185
End Page
190
DOI
10.1016/j.clcc.2011.11.003

Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.

PURPOSE: To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. EXPERIMENT DESIGN: Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. RESULTS: Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. CONCLUSIONS: Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Authors
Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI
MLA Citation
Strickler, JH, Starodub, AN, Jia, J, Meadows, KL, Nixon, AB, Dellinger, A, Morse, MA, Uronis, HE, Marcom, PK, Zafar, SY, Haley, ST, and Hurwitz, HI. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemother Pharmacol 70.2 (August 2012): 251-258.
PMID
22744359
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
2
Publish Date
2012
Start Page
251
End Page
258
DOI
10.1007/s00280-012-1911-1

A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors.

PURPOSE: Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. METHODS: Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. RESULTS: Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. CONCLUSIONS: The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

Authors
Vlahovic, G; Meadows, KL; Uronis, HE; Morse, MA; Blobe, GC; Riedel, RF; Zafar, SY; Alvarez-Secord, A; Gockerman, J; Starodub, AN; Ready, NE; Anderson, EL; Bendell, JC; Hurwitz, HI
MLA Citation
Vlahovic, G, Meadows, KL, Uronis, HE, Morse, MA, Blobe, GC, Riedel, RF, Zafar, SY, Alvarez-Secord, A, Gockerman, J, Starodub, AN, Ready, NE, Anderson, EL, Bendell, JC, and Hurwitz, HI. "A phase I study of bevacizumab, everolimus and panitumumab in advanced solid tumors." Cancer Chemother Pharmacol 70.1 (July 2012): 95-102.
PMID
22638798
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
1
Publish Date
2012
Start Page
95
End Page
102
DOI
10.1007/s00280-012-1889-8

Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer.

Despite advances in contemporary chemotherapeutic strategies, long-term survival still remains elusive for patients with metastatic colorectal cancer. A better understanding of the molecular markers of drug sensitivity to match therapy with patient is needed to improve clinical outcomes. In this study, we used in vitro drug sensitivity data from the NCI-60 cell lines together with their Affymetrix microarray data to develop a gene expression signature to predict sensitivity to oxaliplatin. To validate our oxaliplatin sensitivity signature, patient-derived colorectal cancer explants (PDCCE) were developed in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice from resected human colorectal tumors. Analysis of gene expression profiles found similarities between the PDCCEs and their parental human tumors, suggesting their utility to study drug sensitivity in vivo. The oxaliplatin sensitivity signature was then validated in vivo with response data from 14 PDCCEs treated with oxaliplatin and was found to have an accuracy of 92.9% (sensitivity = 87.5%; specificity = 100%). Our findings suggest that PDCCEs can be a novel source to study drug sensitivity in colorectal cancer. Furthermore, genomic-based analysis has the potential to be incorporated into future strategies to optimize individual therapy for patients with metastatic colorectal cancer.

Authors
Kim, MK; Osada, T; Barry, WT; Yang, XY; Freedman, JA; Tsamis, KA; Datto, M; Clary, BM; Clay, T; Morse, MA; Febbo, PG; Lyerly, HK; Hsu, DS
MLA Citation
Kim, MK, Osada, T, Barry, WT, Yang, XY, Freedman, JA, Tsamis, KA, Datto, M, Clary, BM, Clay, T, Morse, MA, Febbo, PG, Lyerly, HK, and Hsu, DS. "Characterization of an oxaliplatin sensitivity predictor in a preclinical murine model of colorectal cancer." Mol Cancer Ther 11.7 (July 2012): 1500-1509.
PMID
22351745
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
11
Issue
7
Publish Date
2012
Start Page
1500
End Page
1509
DOI
10.1158/1535-7163.MCT-11-0937

Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells.

INTRODUCTION: Sustained HER2 signaling at the cell surface is an oncogenic mechanism in a significant proportion of breast cancers. While clinically effective therapies targeting HER2 such as mAbs and tyrosine kinase inhibitors exist, tumors overexpressing HER2 eventually progress despite treatment. Thus, abrogation of persistent HER2 expression at the plasma membrane to synergize with current approaches may represent a novel therapeutic strategy. METHODS: We generated polyclonal anti-HER2 antibodies (HER2-VIA) by vaccinating mice with an adenovirus expressing human HER2, and assessed their signaling effects in vitro and anti-tumor effects in a xenograft model. In addition, we studied the signaling effects of human HER2-specific antibodies induced by vaccinating breast cancer patients with a HER2 protein vaccine. RESULTS: HER2-VIA bound HER2 at the plasma membrane, initially activating the downstream kinases extracellular signal-regulated protein kinase 1/2 and Akt, but subsequently inducing receptor internalization in clathrin-coated pits in a HER2 kinase-independent manner, followed by ubiquitination and degradation of HER2 into a 130 kDa fragment phosphorylated at tyrosine residues 1,221/1,222 and 1,248. Following vaccination of breast cancer patients with the HER2 protein vaccine, HER2-specific antibodies were detectable and these antibodies bound to cell surface-expressed HER2 and inhibited HER2 signaling through blocking tyrosine 877 phosphorylation of HER2. In contrast to the murine antibodies, human anti-HER2 antibodies induced by protein vaccination did not mediate receptor internalization and degradation. CONCLUSION: These data provide new insight into HER2 trafficking at the plasma membrane and the changes induced by polyclonal HER2-specific antibodies. The reduction of HER2 membrane expression and HER2 signaling by polyclonal antibodies induced by adenoviral HER2 vaccines supports human clinical trials with this strategy for those breast cancer patients with HER2 therapy-resistant disease.

Authors
Ren, X-R; Wei, J; Lei, G; Wang, J; Lu, J; Xia, W; Spector, N; Barak, LS; Clay, TM; Osada, T; Hamilton, E; Blackwell, K; Hobeika, AC; Morse, MA; Lyerly, HK; Chen, W
MLA Citation
Ren, X-R, Wei, J, Lei, G, Wang, J, Lu, J, Xia, W, Spector, N, Barak, LS, Clay, TM, Osada, T, Hamilton, E, Blackwell, K, Hobeika, AC, Morse, MA, Lyerly, HK, and Chen, W. "Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells. (Published online)" Breast Cancer Res 14.3 (June 7, 2012): R89-.
PMID
22676470
Source
pubmed
Published In
Breast Cancer Research
Volume
14
Issue
3
Publish Date
2012
Start Page
R89
DOI
10.1186/bcr3204

Novel recombinant alphaviral and adenoviral vectors for cancer immunotherapy.

Although cellular immunotherapy based on autolgous dendritic cells (DCs) targeting antigens expressed by metastatic cancer has demonstrated clinical efficacy, the logistical challenges in generating an individualized cell product create an imperative to develop alternatives to DC-based cancer vaccines. Particularly attractive alternatives include in situ delivery of antigen and activation signals to resident antigen-presenting cells (APCs), which can be achieved by novel fusion molecules targeting the mannose receptor and by recombinant viral vectors expressing the antigen of interest and capable of infecting DCs. A particular challenge in the use of viral vectors is the well-appreciated clinical obstacles to their efficacy, specifically vector-specific neutralizing immune responses. Because heterologous prime and boost strategies have been demonstrated to be particularly potent, we developed two novel recombinant vectors based on alphaviral replicon particles and a next-generation adenovirus encoding an antigen commonly overexpressed in many human cancers, carcinoembryonic antigen (CEA). The rationale for developing these vectors, their unique characteristics, the preclinical studies and early clinical experience with each, and opportunities to enhance their effectiveness will be reviewed. The potential of each of these potent recombinant vectors to efficiently generate clinically active anti-tumor immune response alone, or in combination, will be discussed.

Authors
Osada, T; Morse, MA; Hobeika, A; Lyerly, HK
MLA Citation
Osada, T, Morse, MA, Hobeika, A, and Lyerly, HK. "Novel recombinant alphaviral and adenoviral vectors for cancer immunotherapy." Semin Oncol 39.3 (June 2012): 305-310. (Review)
PMID
22595053
Source
pubmed
Published In
Seminars in Oncology
Volume
39
Issue
3
Publish Date
2012
Start Page
305
End Page
310
DOI
10.1053/j.seminoncol.2012.02.013

Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function.

CD4+CD25+regulatory T cells (T(reg)) impair anti-tumor and anti-viral immunity. As there are higher T(reg) levels in cancer patients compared with healthy individuals, there is considerable interest in eliminating them or altering their function as part of cancer or viral immunotherapy strategies. The scurfin transcriptional regulator encoded by the member of the forkhead winged helix protein family (FOXP3) is critical for maintaining the functions of T(reg). We hypothesized that targeting FOXP3 expression with a novel arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino (PPMO) based antisense would eliminate T(reg) and enhance the induction of effector T-cell responses. We observed that the PPMO was taken up by activated T cells in vitro and could downregulate FOXP3 expression, which otherwise increases during antigen-specific T-cell activation. Generation of antigen-specific T cells in response to peptide stimulation was enhanced by pre-treatment of peripheral blood mononuclear cells with the FOXP3-targeted PPMO. In summary, modulation of T(reg) levels using the FOXP3 PPMO antisense-based genomic strategy has the potential to optimize immunotherapy strategies in cancer and viral immunotherapy.

Authors
Morse, MA; Hobeika, A; Serra, D; Aird, K; McKinney, M; Aldrich, A; Clay, T; Mourich, D; Lyerly, HK; Iversen, PL; Devi, GR
MLA Citation
Morse, MA, Hobeika, A, Serra, D, Aird, K, McKinney, M, Aldrich, A, Clay, T, Mourich, D, Lyerly, HK, Iversen, PL, and Devi, GR. "Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function." Cancer Gene Ther 19.1 (January 2012): 30-37.
PMID
21997230
Source
pubmed
Published In
Cancer Gene Therapy
Volume
19
Issue
1
Publish Date
2012
Start Page
30
End Page
37
DOI
10.1038/cgt.2011.63

Histological and molecular evaluation of patient-derived colorectal cancer explants.

Mouse models have been developed to investigate colorectal cancer etiology and evaluate new anti-cancer therapies. While genetically engineered and carcinogen-induced mouse models have provided important information with regard to the mechanisms underlying the oncogenic process, tumor xenograft models remain the standard for the evaluation of new chemotherapy and targeted drug treatments for clinical use. However, it remains unclear to what extent explanted colorectal tumor tissues retain inherent pathological features over time. In this study, we have generated a panel of 27 patient-derived colorectal cancer explants (PDCCEs) by direct transplantation of human colorectal cancer tissues into NOD-SCID mice. Using this panel, we performed a comparison of histology, gene expression and mutation status between PDCCEs and the original human tissues from which they were derived. Our findings demonstrate that PDCCEs maintain key histological features, basic gene expression patterns and KRAS/BRAF mutation status through multiple passages. Altogether, these findings suggest that PDCCEs maintain similarity to the patient tumor from which they are derived and may have the potential to serve as a reliable preclinical model that can be incorporated into future strategies to optimize individual therapy for patients with colorectal cancer.

Authors
Uronis, JM; Osada, T; McCall, S; Yang, XY; Mantyh, C; Morse, MA; Lyerly, HK; Clary, BM; Hsu, DS
MLA Citation
Uronis, JM, Osada, T, McCall, S, Yang, XY, Mantyh, C, Morse, MA, Lyerly, HK, Clary, BM, and Hsu, DS. "Histological and molecular evaluation of patient-derived colorectal cancer explants." PLoS One 7.6 (2012): e38422-.
PMID
22675560
Source
pubmed
Published In
PloS one
Volume
7
Issue
6
Publish Date
2012
Start Page
e38422
DOI
10.1371/journal.pone.0038422

First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients

Background: DepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907.Methods: A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol.Results: DPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3), most of ovarian (5/6) and one third of prostate (3/9) cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients) after the first vaccination. In 83% of immune responders (50% of evaluable patients), peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients) showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines.Conclusions: The novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be immune competent. © 2012 Berinstein et al.; licensee BioMed Central Ltd.

Authors
Berinstein, NL; Karkada, M; Morse, MA; Nemunaitis, JJ; Chatta, G; Kaufman, H; Odunsi, K; Nigam, R; Sammatur, L; MacDonald, LD; Weir, GM; Stanford, MM; Mansour, M
MLA Citation
Berinstein, NL, Karkada, M, Morse, MA, Nemunaitis, JJ, Chatta, G, Kaufman, H, Odunsi, K, Nigam, R, Sammatur, L, MacDonald, LD, Weir, GM, Stanford, MM, and Mansour, M. "First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients." Journal of Translational Medicine 10.1 (2012).
PMID
22862954
Source
scival
Published In
Journal of Translational Medicine
Volume
10
Issue
1
Publish Date
2012
DOI
10.1186/1479-5876-10-156

Lonafarnib for cancer and progeria

Introduction: Lonafarnib is a non-peptidomimetic inhibitor of farnesyl transferase, an enzyme responsible for the post-translational lipid modification of a wide variety of cellular proteins that are involved in the pathogenic pathways of various diseases including cancer and progeria. Although extensive clinical research indicates limited activity of lonafarnib in solid tumors, there is recent interest in combinations of farnesyl transferase inhibitors with imatinib or bortezomib in hematological malignancies and to investigate the role of lonafarnib in progeria. Areas covered: This review examines the in vitro and in vivo pharmacology of lonafarnib and the available clinical data for lonafarnib monotherapy and combination therapy in the treatment of solid and hematological malignancies as well as progeria, using studies identified from the PubMed database supplemented by computerized search of relevant abstracts from major cancer and hematology conferences. Expert opinion: There is no evidence to support the use of lonafarnib in solid tumors. There is ongoing interest to explore lonafarnib for progeria and to investigate other farnesyl transferase inhibitors for chronic and acute leukemias. © 2012 Informa UK, Ltd.

Authors
Wong, NS; Morse, MA
MLA Citation
Wong, NS, and Morse, MA. "Lonafarnib for cancer and progeria." Expert Opinion on Investigational Drugs 21.7 (2012): 1043-1055.
PMID
22620979
Source
scival
Published In
Expert Opinion on Investigational Drugs
Volume
21
Issue
7
Publish Date
2012
Start Page
1043
End Page
1055
DOI
10.1517/13543784.2012.688950

P1-13-03: Zoledronic Acid Induces an Immune Response in Breast Cancer Patients through Stimulation of Central Memory and Effector Memory gamma/delta T-Cells.

Authors
Hamilton, EP; Hobeika, AC; Lyerly, HK; Owzar, K; Rocha, G; Kimmick, GG; Marcom, PK; Peppercorn, JM; Morse, MA; Blackwell, KL
MLA Citation
Hamilton, EP, Hobeika, AC, Lyerly, HK, Owzar, K, Rocha, G, Kimmick, GG, Marcom, PK, Peppercorn, JM, Morse, MA, and Blackwell, KL. "P1-13-03: Zoledronic Acid Induces an Immune Response in Breast Cancer Patients through Stimulation of Central Memory and Effector Memory gamma/delta T-Cells." Cancer Research 71.24 Supplement (December 15, 2011): P1-13-03-P1-13-03.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
24 Supplement
Publish Date
2011
Start Page
P1-13-03
End Page
P1-13-03
DOI
10.1158/0008-5472.SABCS11-P1-13-03

Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells.

Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting the immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. Using in vitro assays with human DCs, we demonstrated that DCs transfected with mRNA encoding a humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a phase I clinical cancer immunotherapy trial.

Authors
Pruitt, SK; Boczkowski, D; de Rosa, N; Haley, NR; Morse, MA; Tyler, DS; Dannull, J; Nair, S
MLA Citation
Pruitt, SK, Boczkowski, D, de Rosa, N, Haley, NR, Morse, MA, Tyler, DS, Dannull, J, and Nair, S. "Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells." Eur J Immunol 41.12 (December 2011): 3553-3563.
PMID
22028176
Source
pubmed
Published In
European Journal of Immunology
Volume
41
Issue
12
Publish Date
2011
Start Page
3553
End Page
3563
DOI
10.1002/eji.201141383

Increasing vaccine potency through exosome antigen targeting.

While many tumor associated antigens (TAAs) have been identified in human cancers, efforts to develop efficient TAA "cancer vaccines" using classical vaccine approaches have been largely ineffective. Recently, a process to specifically target proteins to exosomes has been established which takes advantage of the ability of the factor V like C1C2 domain of lactadherin to specifically address proteins to exosomes. Using this approach, we hypothesized that TAAs could be targeted to exosomes to potentially increase their immunogenicity, as exosomes have been demonstrated to traffic to antigen presenting cells (APC). To investigate this possibility, we created adenoviral vectors expressing the extracellular domain (ECD) of two non-mutated TAAs often found in tumors of cancer patients, carcinoembryonic antigen (CEA) and HER2, and coupled them to the C1C2 domain of lactadherin. We found that these C1C2 fusion proteins had enhanced expression in exosomes in vitro. We saw significant improvement in antigen specific immune responses to each of these antigens in naïve and tolerant transgenic animal models and could further demonstrate significantly enhanced therapeutic anti-tumor effects in a human HER2+ transgenic animal model. These findings demonstrate that the mode of secretion and trafficking can influence the immunogenicity of different human TAAs, and may explain the lack of immunogenicity of non-mutated TAAs found in cancer patients. They suggest that exosomal targeting could enhance future anti-tumor vaccination protocols. This targeting exosome process could also be adapted for the development of more potent vaccines in some viral and parasitic diseases where the classical vaccine approach has demonstrated limitations.

Authors
Hartman, ZC; Wei, J; Glass, OK; Guo, H; Lei, G; Yang, X-Y; Osada, T; Hobeika, A; Delcayre, A; Le Pecq, J-B; Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Hartman, ZC, Wei, J, Glass, OK, Guo, H, Lei, G, Yang, X-Y, Osada, T, Hobeika, A, Delcayre, A, Le Pecq, J-B, Morse, MA, Clay, TM, and Lyerly, HK. "Increasing vaccine potency through exosome antigen targeting." Vaccine 29.50 (November 21, 2011): 9361-9367.
PMID
22001882
Source
pubmed
Published In
Vaccine
Volume
29
Issue
50
Publish Date
2011
Start Page
9361
End Page
9367
DOI
10.1016/j.vaccine.2011.09.133

Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma.

PURPOSE: Extrahepatic cholangiocarcinoma is an uncommon but lethal malignancy. We analyzed the role of definitive chemoradiotherapy for patients with nonmetastatic, locally advanced extrahepatic cholangiocarcinoma treated at a single institution. METHODS AND MATERIALS: This retrospective analysis included 37 patients who underwent external beam radiation therapy (EBRT) with concurrent chemotherapy and/or brachytherapy (BT) for locally advanced extrahepatic cholangiocarcinoma. Local control (LC) and overall survival (OS) were assessed, and univariate regression analysis was used to evaluate the effects of patient- and treatment-related factors on clinical outcomes. RESULTS: Twenty-three patients received EBRT alone, 8 patients received EBRT plus BT, and 6 patients received BT alone (median follow-up of 14 months). Two patients were alive without evidence of recurrence at the time of analysis. Actuarial OS and LC rates at 1 year were 59% and 90%, respectively, and 22% and 71%, respectively, at 2 years. Two patients lived beyond 5 years without evidence of recurrence. On univariate analysis, EBRT with or without BT improved LC compared to BT alone (97% vs. 56% at 1 year; 75% vs. 56% at 2 years; p = 0.096). Patients who received EBRT alone vs. BT alone also had improved LC (96% vs. 56% at 1 year; 80% vs. 56% at 2 years; p = 0.113). Age, gender, tumor location (proximal vs. distal), histologic differentiation, EBRT dose (≤ or >50 Gy), EBRT planning method (two-dimensional vs. three-dimensional), and chemotherapy were not associated with patient outcomes. CONCLUSIONS: Patients with locally advanced extrahepatic cholangiocarcinoma have poor survival. Long-term survival is rare. The majority of patients treated with EBRT had local control at the time of death, suggesting that symptoms due to the local tumor effect might be effectively controlled with radiation therapy, and EBRT is an important element of treatment. Novel treatment approaches are indicated in the therapy for this disease.

Authors
Ghafoori, AP; Nelson, JW; Willett, CG; Chino, J; Tyler, DS; Hurwitz, HI; Uronis, HE; Morse, MA; Clough, RW; Czito, BG
MLA Citation
Ghafoori, AP, Nelson, JW, Willett, CG, Chino, J, Tyler, DS, Hurwitz, HI, Uronis, HE, Morse, MA, Clough, RW, and Czito, BG. "Radiotherapy in the treatment of patients with unresectable extrahepatic cholangiocarcinoma." Int J Radiat Oncol Biol Phys 81.3 (November 1, 2011): 654-659.
PMID
20864265
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
81
Issue
3
Publish Date
2011
Start Page
654
End Page
659
DOI
10.1016/j.ijrobp.2010.06.018

A phase I multicenter study of continuous oral administration of lonafarnib (SCH 66336) and intravenous gemcitabine in patients with advanced cancer.

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics, and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8, and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hr; median T(max) values ranged from 4 to 8 hr. Two patients had partial response; seven patients had stable disease at least 6 months. Oral lonafarnib at 150 mg a.m./100 mg p.m. plus gemcitabine at 1,000 mg/m(2) is the maximum tolerated dose with acceptable safety and tolerability.

Authors
Wong, NS; Meadows, KL; Rosen, LS; Adjei, AA; Kaufmann, SH; Morse, MA; Petros, WP; Zhu, Y; Statkevich, P; Cutler, DL; Meyers, ML; Hurwitz, HI
MLA Citation
Wong, NS, Meadows, KL, Rosen, LS, Adjei, AA, Kaufmann, SH, Morse, MA, Petros, WP, Zhu, Y, Statkevich, P, Cutler, DL, Meyers, ML, and Hurwitz, HI. "A phase I multicenter study of continuous oral administration of lonafarnib (SCH 66336) and intravenous gemcitabine in patients with advanced cancer." Cancer Invest 29.9 (November 2011): 617-625.
PMID
22011284
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
29
Issue
9
Publish Date
2011
Start Page
617
End Page
625
DOI
10.3109/07357907.2011.621912

Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells.

Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg cells and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. In human in vitro assays, we demonstrated that DCs transfected with mRNA encoding humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a Phase I clinical cancer immunotherapy trial.

Authors
Pruitt, SK; Boczkowski, D; de Rosa, N; Haley, NR; Morse, MA; Tyler, DS; Dannull, J; Nair, S
MLA Citation
Pruitt, SK, Boczkowski, D, de Rosa, N, Haley, NR, Morse, MA, Tyler, DS, Dannull, J, and Nair, S. "Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells." Eur J Immunol (September 9, 2011).
PMID
21905021
Source
pubmed
Published In
European Journal of Immunology
Publish Date
2011
DOI
10.1002/eji.201041383

A phase II study of oxaliplatin, dose-intense capecitabine, and high-dose bevacizumab in the treatment of metastatic colorectal cancer.

BACKGROUND: This study was designed to determine the efficacy and tolerability of a novel 2-week regimen of capecitabine, oxaliplatin (OHP), and bevacizumab in patients with chemo-naive advanced colorectal cancer. PATIENTS AND METHODS: Nineteen patients with previously untreated advanced colorectal cancer received capecitabine at 1000 mg/m(2) twice a day on days 1-5 and days 8-12 of a 14-day cycle, and OHP at 85 mg/m(2) and bevacizumab at 10 mg/kg every 2 weeks. Because of unacceptable toxicities, the capecitabine dose was reduced to 850 mg/m(2). Thirty-one additional patients were treated at the lower capecitabine dose. Treatment continued until disease progression, persistent intolerable toxicity, or physician and/or patient discretion. RESULTS: Overall, toxicities were better managed and tolerated at the 850 mg/-m(2) capecitabine dose. The most common treatment-related grade ≥ 3 toxicities were diarrhea and sensory neuropathy. In the first 19 subjects, the response rate was 63% (95% confidence interval [CI], 38%-84%) and 5 patients had stable disease; median progression-free survival (PFS) was 10.1 months (95% CI, 5.7-19.5 months). In the subsequent 31 patients, the response was 42% (95% CI, 25%-61%); 11 patients had stable disease and median PFS was 10.4 months (95% CI, 6.9-15.4); median overall survival was 24.8 months (95% CI, 12.9-39.7). CONCLUSIONS: This novel regimen of capecitabine at 850 mg/m(2) twice a day on days 1-5 and days 8-12 and OHP at 85 mg/m(2)and bevacizumab at 10 mg/kg every 14 days is clinically active in advanced colorectal cancer. The toxicity profile of this regimen is consistent with the standard every-3-week dosing schedule.

Authors
Wong, NS; Fernando, NH; Bendell, JC; Morse, MA; Blobe, GC; Honeycutt, W; Pang, H; Hurwitz, HI
MLA Citation
Wong, NS, Fernando, NH, Bendell, JC, Morse, MA, Blobe, GC, Honeycutt, W, Pang, H, and Hurwitz, HI. "A phase II study of oxaliplatin, dose-intense capecitabine, and high-dose bevacizumab in the treatment of metastatic colorectal cancer." Clin Colorectal Cancer 10.3 (September 2011): 210-216.
PMID
21855046
Source
pubmed
Published In
Clinical colorectal cancer
Volume
10
Issue
3
Publish Date
2011
Start Page
210
End Page
216
DOI
10.1016/j.clcc.2011.03.018

Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients.

PURPOSE: The use of tumor-derived proteins as cancer vaccines is complicated by tolerance to these self-antigens. Tolerance may be broken by immunization with activated, autologous, ex vivo generated and antigen-loaded, antigen-presenting cells (APC); however, targeting tumor antigen directly to APC in vivo would be a less complicated strategy. We wished to test whether targeted delivery of an otherwise poorly immunogenic, soluble antigen to APC through their mannose receptors (MR) would induce clinically relevant immunity. EXPERIMENTAL DESIGN: Two phase I studies were conducted with CDX-1307, a vaccine composed of human chorionic gonadotropin beta-chain (hCG-β) fused to an MR-specific monoclonal antibody, administered either locally (intradermally) or systemically (intravenously) in patients with advanced epithelial malignancies. An initial dose escalation of single-agent CDX-1307 was followed by additional cohorts of CDX-1307 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) and the Toll-like receptor (TLR) 3 agonist polyinosinic-polycytidylic acid (poly-ICLC) and TLR7/8 agonist resiquimod to activate the APC. RESULTS: CDX-1307 induced consistent humoral and T-cell responses to hCG-β when coadministered with TLR agonists. Greater immune responses and clinical benefit, including the longest duration of stable disease, were observed with immunization combined with local TLR agonists. Immune responses were induced equally efficiently in patients with elevated and nonelevated levels of serum hCG-β. Antibodies within the serum of vaccinated participants had tumor suppressive function in vitro. Toxicity consisted chiefly of mild injection site reactions. CONCLUSIONS: APC targeting and activation induce adaptive immunity against poorly immunogenic self-antigens which has implications for enhancing the efficacy of cancer immunotherapy.

Authors
Morse, MA; Chapman, R; Powderly, J; Blackwell, K; Keler, T; Green, J; Riggs, R; He, L-Z; Ramakrishna, V; Vitale, L; Zhao, B; Butler, SA; Hobeika, A; Osada, T; Davis, T; Clay, T; Lyerly, HK
MLA Citation
Morse, MA, Chapman, R, Powderly, J, Blackwell, K, Keler, T, Green, J, Riggs, R, He, L-Z, Ramakrishna, V, Vitale, L, Zhao, B, Butler, SA, Hobeika, A, Osada, T, Davis, T, Clay, T, and Lyerly, HK. "Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with Toll-like receptor stimulation to induce immunity to self-antigens in cancer patients." Clin Cancer Res 17.14 (July 15, 2011): 4844-4853.
PMID
21632857
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
14
Publish Date
2011
Start Page
4844
End Page
4853
DOI
10.1158/1078-0432.CCR-11-0891

HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.

HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers.

Authors
Hartman, ZC; Yang, X-Y; Glass, O; Lei, G; Osada, T; Dave, SS; Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Hartman, ZC, Yang, X-Y, Glass, O, Lei, G, Osada, T, Dave, SS, Morse, MA, Clay, TM, and Lyerly, HK. "HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis." Cancer Res 71.13 (July 1, 2011): 4380-4391.
PMID
21518778
Source
pubmed
Published In
Cancer Research
Volume
71
Issue
13
Publish Date
2011
Start Page
4380
End Page
4391
DOI
10.1158/0008-5472.CAN-11-0308

Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

Authors
Osada, T; Chen, M; Yang, XY; Spasojevic, I; Vandeusen, JB; Hsu, D; Clary, BM; Clay, TM; Chen, W; Morse, MA; Lyerly, HK
MLA Citation
Osada, T, Chen, M, Yang, XY, Spasojevic, I, Vandeusen, JB, Hsu, D, Clary, BM, Clay, TM, Chen, W, Morse, MA, and Lyerly, HK. "Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations." Cancer Res 71.12 (June 15, 2011): 4172-4182.
PMID
21531761
Source
pubmed
Published In
Cancer Research
Volume
71
Issue
12
Publish Date
2011
Start Page
4172
End Page
4182
DOI
10.1158/0008-5472.CAN-10-3978

Incidence and predictors of cetuximab hypersensitivity reactions in a North Carolina academic medical center.

OBJECTIVES: Previous research has indicated a high incidence of cetuximab hypersensitivity reactions in the southern US. This study documents the incidence of hypersensitivity reactions in North Carolina, and explores whether factors such as patient demographics, allergy history, premedications, and cancer type are potential predictors for cetuximab reactions. METHODS: This retrospective chart review consisted of 72 consecutively treated patients from Duke University's Morris Oncology treatment center between September 2005 and August 2007. Data regarding stage of malignancy, premedications, and hypersensitivity reactions were collected from electronic databases. The number and type of reactions were characterized. Patients with and without hypersensitivity reactions were compared using bivariate statistics and multivariate logistic regression. RESULTS: Of the 72 patients, 21 (29%) experienced hypersensitivity reactions. The majority of reactions (62%) were grades III or IV. Of the 21 patients having a reaction, 9 (43%) were sent to the emergency room and 5 (24%) had an overnight hospitalization. Three hospitalized patients were admitted to the intensive care unit. Both male gender (p = 0.039) and head/neck cancer (p = 0.014) were related to an increased likelihood of hypersensitivity reaction in bivariate analyses. In multivariate analyses, controlling for demographics, allergy history, premedications, and cancer type/stage, only type of cancer was predictive of hypersensitivity reaction (colon vs head/neck OR = 0.177; 95% CI 0.036-0.858). CONCLUSION: This study confirms a high rate of cetuximab hypersensitivity reactions in a southern region of the US. Patients with head/neck cancers were significantly more likely to have hypersensitivity reactions than patients with colon cancers.

Authors
Hansen, NL; Chandiramani, DV; Morse, MA; Wei, D; Hedrick, NE; Hansen, RA
MLA Citation
Hansen, NL, Chandiramani, DV, Morse, MA, Wei, D, Hedrick, NE, and Hansen, RA. "Incidence and predictors of cetuximab hypersensitivity reactions in a North Carolina academic medical center." J Oncol Pharm Pract 17.2 (June 2011): 125-130.
PMID
20147576
Source
pubmed
Published In
Journal of Oncology Pharmacy Practice
Volume
17
Issue
2
Publish Date
2011
Start Page
125
End Page
130
DOI
10.1177/1078155209360853

CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer.

Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-β chain (hCG-β), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-β-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-β-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit.

Authors
Morse, MA; Bradley, DA; Keler, T; Laliberte, RJ; Green, JA; Davis, TA; Inman, BA
MLA Citation
Morse, MA, Bradley, DA, Keler, T, Laliberte, RJ, Green, JA, Davis, TA, and Inman, BA. "CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer." Expert Rev Vaccines 10.6 (June 2011): 733-742. (Review)
PMID
21692696
Source
pubmed
Published In
Expert Review of Vaccines
Volume
10
Issue
6
Publish Date
2011
Start Page
733
End Page
742
DOI
10.1586/erv.11.20

Liver Transplantation Following Down-Staging of a Large Primary Liver Tumor Associated with a Very High Serum Alpha Fetoprotein Concentration

Authors
Smith, AD; Muir, AJ; Morse, MA; Suhocki, PV; Ravindra, KV
MLA Citation
Smith, AD, Muir, AJ, Morse, MA, Suhocki, PV, and Ravindra, KV. "Liver Transplantation Following Down-Staging of a Large Primary Liver Tumor Associated with a Very High Serum Alpha Fetoprotein Concentration." June 2011.
Source
wos-lite
Published In
Liver Transplantation
Volume
17
Issue
6
Publish Date
2011
Start Page
S275
End Page
S276

MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer.

PURPOSE: The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans. EXPERIMENTAL DESIGN: Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancer-associated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials. RESULTS: T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells. CONCLUSION: Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor-specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients.

Authors
Morse, MA; Secord, AA; Blackwell, K; Hobeika, AC; Sinnathamby, G; Osada, T; Hafner, J; Philip, M; Clay, TM; Lyerly, HK; Philip, R
MLA Citation
Morse, MA, Secord, AA, Blackwell, K, Hobeika, AC, Sinnathamby, G, Osada, T, Hafner, J, Philip, M, Clay, TM, Lyerly, HK, and Philip, R. "MHC class I-presented tumor antigens identified in ovarian cancer by immunoproteomic analysis are targets for T-cell responses against breast and ovarian cancer." Clin Cancer Res 17.10 (May 15, 2011): 3408-3419.
PMID
21300761
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
10
Publish Date
2011
Start Page
3408
End Page
3419
DOI
10.1158/1078-0432.CCR-10-2614

MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response.

The development of potent cancer vaccines for common malignancies such as lung cancer requires identification of suitable target antigens. We hypothesized that peptide epitopes naturally presented by MHC class I molecules on the surface of cancer cells would be the most relevant targets. We used LC/MS/MS analysis and identified 68 MHC class I-presented peptides from lung cancer cells. Using the criteria of strong consensus for HLA-A2 binding and relevance of the source proteins to malignant phenotype, we selected 8 peptides for functional characterization. These peptides, with a range of binding affinities, were confirmed to stabilize HLA-A2 molecules and were used to activate peptide-specific CTLs that efficiently recognized lung tumor cells. No correlation between the transcript levels of the source proteins and the extent of peptide-specific T cell recognition of lung cancer cells was observed. Furthermore, the peptide specific CTLs failed to recognize HLA-A2+ normal lung cells despite expression of the mRNA encoding the source proteins from which the peptides were derived. We conclude that MHC class I associated peptide epitopes are a more relevant source of authentic tumor antigens than over-expressed proteins and the identified peptides may be used as antigens for therapeutic vaccine strategies to treat lung cancer.

Authors
Shetty, V; Sinnathamby, G; Nickens, Z; Shah, P; Hafner, J; Mariello, L; Kamal, S; Vlahović, G; Lyerly, HK; Morse, MA; Philip, R
MLA Citation
Shetty, V, Sinnathamby, G, Nickens, Z, Shah, P, Hafner, J, Mariello, L, Kamal, S, Vlahović, G, Lyerly, HK, Morse, MA, and Philip, R. "MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response." J Proteomics 74.5 (May 1, 2011): 728-743.
PMID
21362506
Source
pubmed
Published In
Journal of Proteomics
Volume
74
Issue
5
Publish Date
2011
Start Page
728
End Page
743
DOI
10.1016/j.jprot.2011.02.020

Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines.

Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.

Authors
Clay, TM; Osada, T; Hartman, ZC; Hobeika, A; Devi, G; Morse, MA; Lyerly, HK
MLA Citation
Clay, TM, Osada, T, Hartman, ZC, Hobeika, A, Devi, G, Morse, MA, and Lyerly, HK. "Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines." Immunol Res 49.1-3 (April 2011): 235-247.
PMID
21136201
Source
pubmed
Published In
Immunologic Research
Volume
49
Issue
1-3
Publish Date
2011
Start Page
235
End Page
247
DOI
10.1007/s12026-010-8186-6

ADAM metallopeptidase domain 17 (ADAM17) is naturally processed through major histocompatibility complex (MHC) class I molecules and is a potential immunotherapeutic target in breast, ovarian and prostate cancers.

Selection of suitable antigens is critical for the development of cancer vaccines. Most desirable are over-expressed cell surface proteins that may serve as targets for both antibodies and T cells, thus maximizing a concerted immune response. Towards this goal, we characterized the relevance of tumour necrosis factor-α-converting enzyme (ADAM17) for such targeted therapeutics. ADAM17 is one of the several metalloproteinases that play a key role in epidermal growth factor receptor (EGFR) signalling and has recently emerged as a new therapeutic target in several tumour types. In the present study, we analysed the expression profile of ADAM17 in a variety of normal and cancer cells of human origin and found that this protein is over-expressed on the surface of several types of cancer cells compared to the normal counterparts. Furthermore, we analysed the presentation of a human leucocyte antigen (HLA)-A2-restricted epitope from ADAM17 protein to specific T cells established from normal donors as well as ovarian cancer patients. Our analysis revealed that the HLA-A2-restricted epitope is processed efficiently and presented by various cancer cells and not by normal cells. Tumour-specific T cell activation results in the secretion of both interferon-γ and granzyme B that can be blocked by HLA-A2 specific antibodies. Collectively, our data present evidence that ADAM17 can be a potential target antigen to devise novel immunotherapeutic strategies against ovarian, breast and prostate cancer.

Authors
Sinnathamby, G; Zerfass, J; Hafner, J; Block, P; Nickens, Z; Hobeika, A; Secord, AA; Lyerly, HK; Morse, MA; Philip, R
MLA Citation
Sinnathamby, G, Zerfass, J, Hafner, J, Block, P, Nickens, Z, Hobeika, A, Secord, AA, Lyerly, HK, Morse, MA, and Philip, R. "ADAM metallopeptidase domain 17 (ADAM17) is naturally processed through major histocompatibility complex (MHC) class I molecules and is a potential immunotherapeutic target in breast, ovarian and prostate cancers." Clin Exp Immunol 163.3 (March 2011): 324-332.
PMID
21175594
Source
pubmed
Published In
Clinical & Experimental Immunology
Volume
163
Issue
3
Publish Date
2011
Start Page
324
End Page
332
DOI
10.1111/j.1365-2249.2010.04298.x

Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted. METHODS: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa. RESULTS: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses. CONCLUSION: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study.

Authors
Castaneda, C; Meadows, KL; Truax, R; Morse, MA; Kaufmann, SH; Petros, WP; Zhu, Y; Statkevich, P; Cutler, DL; Hurwitz, HI
MLA Citation
Castaneda, C, Meadows, KL, Truax, R, Morse, MA, Kaufmann, SH, Petros, WP, Zhu, Y, Statkevich, P, Cutler, DL, and Hurwitz, HI. "Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors." Cancer Chemother Pharmacol 67.2 (February 2011): 455-463.
PMID
20972873
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
67
Issue
2
Publish Date
2011
Start Page
455
End Page
463
DOI
10.1007/s00280-010-1488-5

A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE).

PURPOSE: VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination. METHODS: Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1. RESULTS: Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020). CONCLUSIONS: The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.

Authors
Bullock, KE; Petros, WP; Younis, I; Uronis, HE; Morse, MA; Blobe, GC; Zafar, SY; Gockerman, JP; Lager, JJ; Truax, R; Meadows, KL; Howard, LA; O'Neill, MM; Broadwater, G; Hurwitz, HI; Bendell, JC
MLA Citation
Bullock, KE, Petros, WP, Younis, I, Uronis, HE, Morse, MA, Blobe, GC, Zafar, SY, Gockerman, JP, Lager, JJ, Truax, R, Meadows, KL, Howard, LA, O'Neill, MM, Broadwater, G, Hurwitz, HI, and Bendell, JC. "A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE)." Cancer Chemother Pharmacol 67.2 (February 2011): 465-474.
PMID
21079958
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
67
Issue
2
Publish Date
2011
Start Page
465
End Page
474
DOI
10.1007/s00280-010-1507-6

A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer.

AIM: This study was designed to determine the efficacy and tolerability of capecitabine, oxaliplatin and bevacizumab in combination with cetuximab as first-line therapy for advanced colorectal cancer. PATIENTS AND METHODS: Patients with previously untreated advanced colorectal cancer received oxaliplatin 130 mg/m² and bevacizumab 7.5 mg/kg every three weeks, capecitabine 850 mg/m² twice daily on days 1-14, and cetuximab at 400 mg/m² load and 250 mg/m² weekly. KRAS, BRAF and PI3K mutation status from paraffin-embedded tumor samples were assessed using real-time polymerase chain reaction. RESULTS: Thirty patients were evaluable for safety and efficacy. One patient had a complete response and 12 patients had a partial response, giving an overall response rate of 43% (95% confidence interval (CI) 25%-63%). Fifteen patients had stable disease. The median time to progression was 10.3 months (95% CI, 6.8-16.3 months). The median overall survival was 18.8 months (95% CI, 14.2-23.7 months). Common grade ≥ 3 non-hematological toxicities were skin rash (37%), sensory neuropathy (27%) and diarrhea (17%). Grade ≥ 3 hematological toxicities were uncommon. Mutations in KRAS, BRAF and PI3K occurred in 34.5%, 10.3% and 10.3% of patients respectively, but did not correlate with treatment outcome. CONCLUSION: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab did not improve the three-drug regimen activity compared to published data and was associated with significant toxicities requiring frequent dose modifications. KRAS, BRAF, and PI3K mutation status were consistent with published literature, but did not affect outcome in this small study.

Authors
Wong, NS; Fernando, NH; Nixon, AB; Cushman, S; Aklilu, M; Bendell, JC; Morse, MA; Blobe, GC; Ashton, J; Pang, H; Hurwitz, HI
MLA Citation
Wong, NS, Fernando, NH, Nixon, AB, Cushman, S, Aklilu, M, Bendell, JC, Morse, MA, Blobe, GC, Ashton, J, Pang, H, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer." Anticancer Res 31.1 (January 2011): 255-261.
PMID
21273607
Source
pubmed
Published In
Anticancer research
Volume
31
Issue
1
Publish Date
2011
Start Page
255
End Page
261

Depletion of human regulatory T cells.

Regulatory T cells (Treg) have become increasingly relevant in the study of human disease including cancer. Treg cells have been shown to inhibit anti-tumor immune responses, and elevated Treg levels have been associated with certain types of cancer. Similarly, depletion of Tregs by various methods can also enhance anti-tumor immune responses. We have found a prevalence of Treg in cancer patients when compared to normal volunteers. In addition, we have shown that the depletion of Treg using the IL-2 fusion protein denileukin diftitox decreased Treg function and increased antigen-specific T cell response to a cancer vaccine. These results indicate the potential for combining Treg depletion with anti-cancer vaccines to enhance tumor antigen-specific immune responses and the need to explore the dose and schedule of Treg depletion strategies in optimizing vaccine efforts.

Authors
Hobeika, AC; Morse, MA; Osada, T; Peplinski, S; Lyerly, HK; Clay, TM
MLA Citation
Hobeika, AC, Morse, MA, Osada, T, Peplinski, S, Lyerly, HK, and Clay, TM. "Depletion of human regulatory T cells." Methods Mol Biol 707 (2011): 219-231.
PMID
21287338
Source
pubmed
Published In
Methods in molecular biology (Clifton, N.J.)
Volume
707
Publish Date
2011
Start Page
219
End Page
231
DOI
10.1007/978-1-61737-979-6_14

A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer.

PURPOSE: For patients with metastatic colorectal cancer (mCRC), no standard therapy exists after progression on 5-fluorouracil, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Preclinical data demonstrated that combined vascular endothelial growth factor and mammalian target of rapamycin inhibition has greater antiangiogenic and antitumor activity than either monotherapy. A phase I study of bevacizumab plus everolimus demonstrated that the combination is safe; activity was seen in several patients with refractory mCRC. METHODS: Fifty patients with refractory mCRC were enrolled and received bevacizumab at 10 mg/kg every 2 weeks and everolimus at 10 mg orally daily. RESULTS: Of the 50 patients enrolled, the median age was 56 years and the median number of prior regimens was four. Forty-seven patients (96%) had prior bevacizumab exposure and 42 patients (84%) had documented progression on prior bevacizumab-based therapy. Forty-nine patients were evaluable for response; eight patients had minor responses (16%) and an additional 15 patients (30%) had stable disease (SD). No complete or partial responses were seen. The median progression-free survival interval was 2.3 months; however, 26% of patients achieved prolonged SD for ≥6 months, and three patients (6%) were on study for >1 year. The median overall survival duration was 8.1 months. The most common grade 1-2 toxicities were mucositis (68%) and hyperlipidemia (64%). Clinically significant grade ≥3 toxicities included hypertension (14%), fistula/abscess/perforation (8%), mucositis (6%), and hemorrhage (2%). CONCLUSIONS: Bevacizumab plus everolimus is generally tolerable but may have risks related to mucosal damage and/or wound healing. Bevacizumab plus everolimus appears to have modest activity in refractory mCRC in patients.

Authors
Altomare, I; Bendell, JC; Bullock, KE; Uronis, HE; Morse, MA; Hsu, SD; Zafar, SY; Blobe, GC; Pang, H; Honeycutt, W; Sutton, L; Hurwitz, HI
MLA Citation
Altomare, I, Bendell, JC, Bullock, KE, Uronis, HE, Morse, MA, Hsu, SD, Zafar, SY, Blobe, GC, Pang, H, Honeycutt, W, Sutton, L, and Hurwitz, HI. "A phase II trial of bevacizumab plus everolimus for patients with refractory metastatic colorectal cancer." Oncologist 16.8 (2011): 1131-1137.
PMID
21795432
Source
pubmed
Published In
The oncologist
Volume
16
Issue
8
Publish Date
2011
Start Page
1131
End Page
1137
DOI
10.1634/theoncologist.2011-0078

Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is frequently resistant to chemotherapy. However, epidermal growth factor receptor (EGFR) inhibition has demonstrated activity in HCC and overcomes chemotherapy resistance in other settings. We studied the efficacy of combining the anti-EGFR antibody cetuximab with capecitabine and oxaliplatin in advanced HCC. Methods: Patients who had chemotherapy-naive advanced/unresectable HCC and any Childs-Pugh-class chronic liver disease (provided bilirubin was <3 mg/dl) received capecitabine 850 mg/m2 bid days 1-14, oxaliplatin 130 mg/m2 day 1, and cetuximab 400 mg/m2 day 1 then 250 mg/m2 weekly for each 21 day cycle. Results: Twenty-nine patients received any protocol therapy, but 24 completed at least one cycle. Of the 24 patients evaluable for response, 3 had a partial response (12.5%, 95% confidence interval [CI], 3-32%) and 17 had stable disease (71%), for a disease control rate of 83%. Of patients with an elevated AFP, 57% had α >50% reduction in AFP. Median time to progression was 4.5 months (95% CI, 3.2-6.4), and overall survival was 4.4 months (95% CI, 2.4-7.3). Most common toxicities included diarrhea (13 patients, 45%), fatigue (12 patients, 41%), and hypomagnesemia (12 patients, 41%). Fatigue (6 patients) and diarrhea (5 patients) were the most common grade 3-4 toxicities. Three patients died within the first 30 days of treatment (one of toxicity, two of liver failure presumed to be related to disease progression). Conclusions: The capecitabine/oxaliplatin/cetuximab combination was tolerable, though diarrhea was pronounced, in this population. The combination was associated with a modest response rate, but a high rate of AFP response and radiographic stable disease. Time to progression and overall survival were shorter than would be expected for treatment with sorafenib. © 2011 by International Society of Gastrointestinal Oncology.

Authors
Sanoff, HK; Bernard, S; Goldberg, RM; Morse, MA; Garcia, R; Woods, L; Moore, DT; O'Neil, BH
MLA Citation
Sanoff, HK, Bernard, S, Goldberg, RM, Morse, MA, Garcia, R, Woods, L, Moore, DT, and O'Neil, BH. "Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma." Gastrointestinal Cancer Research 4.3 (2011): 78-83.
Source
scival
Published In
Gastrointestinal Cancer Research
Volume
4
Issue
3
Publish Date
2011
Start Page
78
End Page
83

Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response.

There is considerable evidence suggesting that a variety of malignancies utilize the TGFβ cytokine to evade immune surveillance mechanisms to facilitate tumor growth and metastatic progression. The recently developed large- and small-molecule TGFβ inhibitors have demonstrated antitumor efficacy in several preclinical tumor models. Further investigation has revealed these agents to be critically dependent upon the host's immune system, suggesting that the inhibition of TGFβ may overcome the immunosuppressive tumor microenvironment and, ultimately, augment the antitumor immune response. These findings strongly support combining this strategy with other immunotherapeutic approaches for the treatment of metastatic cancer. This review discusses the immunoregulatory and antitumor properties of these pharmacological inhibitors of TGFβ signaling as either independent agents or in combination with various immunotherapeutic strategies, their potential side effects, as well as additional avenues of research that may be necessary for their eventual clinical application.

Authors
Hanks, BA; Morse, MA
MLA Citation
Hanks, BA, and Morse, MA. "Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response." Curr Opin Investig Drugs 11.12 (December 2010): 1342-1353. (Review)
PMID
21154116
Source
pubmed
Published In
Current Opinion in Investigational Drugs
Volume
11
Issue
12
Publish Date
2010
Start Page
1342
End Page
1353

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer.

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

Authors
Morse, MA; Hobeika, AC; Osada, T; Berglund, P; Hubby, B; Negri, S; Niedzwiecki, D; Devi, GR; Burnett, BK; Clay, TM; Smith, J; Lyerly, HK
MLA Citation
Morse, MA, Hobeika, AC, Osada, T, Berglund, P, Hubby, B, Negri, S, Niedzwiecki, D, Devi, GR, Burnett, BK, Clay, TM, Smith, J, and Lyerly, HK. "An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer." J Clin Invest 120.9 (September 2010): 3234-3241.
Website
http://hdl.handle.net/10161/4330
PMID
20679728
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
120
Issue
9
Publish Date
2010
Start Page
3234
End Page
3241
DOI
10.1172/JCI42672

Immune signatures predict prognosis in localized cancer.

The host immune response can impact cancer growth, prognosis, and response to therapy. In colorectal cancer, the presence of cells involved with T-cell-mediated adaptive immunity predicts survival better than the current staging method. We used the expression of genes recently associated with host immune responses (T(H1)-mediated adaptive immunity, inflammation, and immune suppression) to perform hierarchical clustering of multiple large cohorts of cancer specimens to determine if immune-related gene expression resulted in clinical significant groupings of tumors. Microarray data from prostate cancer (n = 79), breast cancer (n = 132), lung cancer (n = 84), glioblastoma multiforme (n = 120), and lymphoma (n = 127) were analyzed. Among adenocarcinomas, the T(H1)-mediated adaptive immunity genes were consistently associated with better prognosis, while genes associated with inflammation and immune suppression were variably associated with outcome. Specifically, increased expression of the T(H1)-mediated adaptive immunity genes was associated with good prognosis in breast cancer patients under 45 years of age (p = .04, hazard ratio [HR] = 0.42) and in prostate cancer patients (p = .03, HR = 0.36) but not in lung cancer patients (p = 0.45, HR = 1.37). In lymphoma, patients with increased expression of inflammation and immune suppression genes had better prognosis than those expressing the T(H1)-mediated adaptive immunity genes (p = .01, HR = 0.43) and in glioblastoma multiforme, the expression of inflammation genes conferred improved prognosis than those expressing immune suppression genes (p = 0.05, HR = 0.62). In aggregate, the gene expression signatures implicating specific components of the immune response hold prognostic import across solid tumors.

Authors
Hsu, DS; Kim, MK; Balakumaran, BS; Acharya, CR; Anders, CK; Clay, T; Lyerly, HK; Drake, CG; Morse, MA; Febbo, PG
MLA Citation
Hsu, DS, Kim, MK, Balakumaran, BS, Acharya, CR, Anders, CK, Clay, T, Lyerly, HK, Drake, CG, Morse, MA, and Febbo, PG. "Immune signatures predict prognosis in localized cancer." Cancer Invest 28.7 (August 2010): 765-773.
PMID
20569070
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
28
Issue
7
Publish Date
2010
Start Page
765
End Page
773
DOI
10.3109/07357900903095755

Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.

The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.

Authors
Morse, MA; Wei, J; Hartman, Z; Xia, W; Ren, X-R; Lei, G; Barry, WT; Osada, T; Hobeika, AC; Peplinski, S; Jiang, H; Devi, GR; Chen, W; Spector, N; Amalfitano, A; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Wei, J, Hartman, Z, Xia, W, Ren, X-R, Lei, G, Barry, WT, Osada, T, Hobeika, AC, Peplinski, S, Jiang, H, Devi, GR, Chen, W, Spector, N, Amalfitano, A, Lyerly, HK, and Clay, TM. "Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo." Int J Cancer 126.12 (June 15, 2010): 2893-2903.
PMID
19856307
Source
pubmed
Published In
International Journal of Cancer
Volume
126
Issue
12
Publish Date
2010
Start Page
2893
End Page
2903
DOI
10.1002/ijc.24995

Adenovirus vaccine immunotherapy targeting WT1-expressing tumors.

IMPORTANCE OF THE FIELD: Tumor associated antigens (TAAs) offer specific targets for developing cancer immunotherapies. In particular, viral vectors encoding transgenic TAAs have been used in recent vaccination strategies. Wilm's Tumor gene (WT1) is a robust TAA which is overexpressed in many malignancies and has been recently used to develop a novel recombinant adenovirus (Ad-WT1) for antitumor immunotherapy. AREAS COVERED IN THIS REVIEW: The lines of evidence over the past two decades leading to the development of Ad-WT1 immunotherapy are reviewed, including preclinical studies and clinical trials using WT1-based vaccines and TAA-expressing adenoviral vectors for antitumor therapy. WHAT THE READER WILL GAIN: The fundamental immunogenic properties of WT1-based vaccines are detailed, as well as the recent progress in using adenoviral vectors for eliciting a TAA-specific immune response. The reader will also gain an understanding of the evidence supporting Ad-WT1 antitumor therapy in vivo. TAKE HOME MESSAGE: Ad-WT1 elicits a potent CD4(+) and CD8(+) T cell immune response and can effectively inhibit tumor growth in vivo, thus making it an important potential cancer therapy worthy of future investigation.

Authors
Clarke, JM; Morse, MA; Lyerly, HK; Clay, T; Osada, T
MLA Citation
Clarke, JM, Morse, MA, Lyerly, HK, Clay, T, and Osada, T. "Adenovirus vaccine immunotherapy targeting WT1-expressing tumors." Expert Opin Biol Ther 10.6 (June 2010): 875-883. (Review)
PMID
20380487
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
10
Issue
6
Publish Date
2010
Start Page
875
End Page
883
DOI
10.1517/14712591003798278

Abstract 5338: Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T cell killing mediated by CEA/CD3-bispecific T cell-engaging BiTE antibody

Authors
Osada, T; Hsu, D; Hammond, S; Hobeika, A; Devi, G; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Osada, T, Hsu, D, Hammond, S, Hobeika, A, Devi, G, Clay, TM, Lyerly, HK, and Morse, MA. "Abstract 5338: Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T cell killing mediated by CEA/CD3-bispecific T cell-engaging BiTE antibody." Cancer Research 70.8 Supplement (April 15, 2010): 5338-5338.
Source
crossref
Published In
Cancer Research
Volume
70
Issue
8 Supplement
Publish Date
2010
Start Page
5338
End Page
5338
DOI
10.1158/1538-7445.AM10-5338

Treatment of Recurrent Intracranial Hemangiopericytoma with SRC-Related Tyrosine Kinase Targeted Therapy: A Case Report.

Hemangiopericytoma (HPC) is a rare sarcomatous tumor arising from pericytes, a support cell found in blood vessels. These tumors can occur throughout the body, particularly in the lower extremities and retroperitoneum. In rare circumstances, HPCs can arise from the meninges. In these cases, they behave similar to meningiomas, in particular angiomatous meningiomas, but tend to be more aggressive and are likely to recur. Treatment usually focuses on surgical resection and radiotherapy with possible inclusion of chemotherapy for control of recurrent disease. We describe a case of recurrent right temporal HPC that first manifested as a paraneoplastic syndrome of oncogenic osteomalacia. Despite maximum therapy, this patient experienced multiple recurrences of the tumor, and immunohistochemical analysis revealed overexpression of platelet-derived growth factor receptor, a member of the SRC-related tyrosine kinases. After multiple recurrences, the patient's tumor has been stable with treatment with monotherapy utilizing molecularly targeted therapy to SRC-related tyrosine kinases. This is the first case report of the treatment of recurrent meningeal HPC with molecularly targeted therapy to SRC-related tyrosine kinases.

Authors
Peters, KB; McLendon, R; Morse, MA; Vredenburgh, JJ
MLA Citation
Peters, KB, McLendon, R, Morse, MA, and Vredenburgh, JJ. "Treatment of Recurrent Intracranial Hemangiopericytoma with SRC-Related Tyrosine Kinase Targeted Therapy: A Case Report. (Published online)" Case Rep Oncol 3.1 (April 8, 2010): 93-97.
PMID
20740166
Source
pubmed
Published In
Case Rep Oncol
Volume
3
Issue
1
Publish Date
2010
Start Page
93
End Page
97
DOI
10.1159/000307468

A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors.

UNLABELLED: The aim of this study was to determine the maximally tolerated dose, recommended phase II dose and toxicity profile of capecitabine plus imatinib mesylate combination. PATIENTS AND METHODS: Twenty-four patients with advanced solid tumors were treated with capecitabine twice daily on days 1-14 and imatinib mesylate once daily on a 21-day cycle. Dose-limiting toxicity was assessed during the first cycle. Treatment continued until disease progression or undesirable toxicity. RESULTS: Six patients were treated with capecitabine at 1000 mg/m(2) and imatinib mesylate 300 mg; unacceptable toxicity due to grade 2 intolerable hand-foot syndrome and/or grade > or = 2 diarrhea was observed. Doses were subsequently reduced to capecitabine at 750 mg/m(2) and imatinib mesylate at 300 mg; toxicities were better tolerated at the lower dose. Dose-limiting toxicities consisted of grade 3 diarrhea, anorexia and fatigue lasting > or = 4 days. Treatment-related adverse events greater than or equal to grade 3 included anemia, diarrhea, dysuria, hypophosphatemia and vertigo. Minor responses were observed in two patients: stable disease > or = 6 months was observed in two out of twenty-one evaluable patients. CONCLUSION: Full doses of capecitabine and imatinib mesylate were not tolerable. The maximum tolerated dose and the recommended phase II dose for this drug combination is capecitabine at 750 mg/m(2) twice daily for 1-14 days and imatinib at 300 mg once daily on a 21-day cycle.

Authors
Dugan, E; Truax, R; Meadows, KL; Nixon, AB; Petros, WP; Favaro, J; Fernando, NH; Morse, MA; Blobe, GC; Hurwitz, HI
MLA Citation
Dugan, E, Truax, R, Meadows, KL, Nixon, AB, Petros, WP, Favaro, J, Fernando, NH, Morse, MA, Blobe, GC, and Hurwitz, HI. "A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors." Anticancer Res 30.4 (April 2010): 1251-1256.
PMID
20530436
Source
pubmed
Published In
Anticancer research
Volume
30
Issue
4
Publish Date
2010
Start Page
1251
End Page
1256

An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity.

PURPOSE: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use. EXPERIMENTAL DESIGN: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo. RESULTS: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo. CONCLUSIONS: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.

Authors
Hartman, ZC; Wei, J; Osada, T; Glass, O; Lei, G; Yang, X-Y; Peplinski, S; Kim, D-W; Xia, W; Spector, N; Marks, J; Barry, W; Hobeika, A; Devi, G; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Hartman, ZC, Wei, J, Osada, T, Glass, O, Lei, G, Yang, X-Y, Peplinski, S, Kim, D-W, Xia, W, Spector, N, Marks, J, Barry, W, Hobeika, A, Devi, G, Amalfitano, A, Morse, MA, Lyerly, HK, and Clay, TM. "An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity." Clin Cancer Res 16.5 (March 1, 2010): 1466-1477.
PMID
20179231
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
16
Issue
5
Publish Date
2010
Start Page
1466
End Page
1477
DOI
10.1158/1078-0432.CCR-09-2549

A year of successful cancer vaccines points to a path forward.

Results from recent clinical trials of the therapeutic vaccines sipuleucel-T (Dendreon Corp), PROSTVAC-VF-TRICOM (National Cancer Institute/BN ImmunoTherapeutics Inc) and BiovaxID (Biovest International Inc) are highlighted. These data support the further development of such vaccines, and provide guidance for the development of improved agents and protocols for the use of therapeutic vaccination to treat cancer.

Authors
Morse, MA; Whelan, M
MLA Citation
Morse, MA, and Whelan, M. "A year of successful cancer vaccines points to a path forward." Curr Opin Mol Ther 12.1 (February 2010): 11-13. (Review)
PMID
20140811
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
12
Issue
1
Publish Date
2010
Start Page
11
End Page
13

Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody.

BACKGROUND: Novel technologies to redirect T-cell killing against cancer cells are emerging. We hypothesised that metastatic human colorectal cancer (CRC) previously treated with conventional chemotherapy would be sensitive to T-cell killing mediated by carcinoembryonic antigen (CEA)/CD3-bispecific T-cell-engaging BiTE antibody (MEDI-565). METHODS: We analysed proliferation and lysis of CEA-positive (CEA+) CRC specimens that had survived previous systemic chemotherapy and biologic therapy to determine whether they could be killed by patient T cells engaged by MEDI-565 in vitro. RESULTS: At low concentrations (0.1-1 ng ml(-1)), MEDI-565+ T cells caused reduced proliferation and enhanced apoptosis of CEA+ human CRC specimens. High levels of soluble CEA did not impair killing by redirected T cells and there was no increase in resistance to T-cell killing despite multiple rounds of exposure. CONCLUSIONS: This study shows for the first time that metastatic CRC specimens derived from patients previously treated with conventional chemotherapy can be lysed by patient T cells. Clinical testing of cancer immunotherapies, such as MEDI-565 that result in exposure of tumours to large numbers of T cells, is warranted.

Authors
Osada, T; Hsu, D; Hammond, S; Hobeika, A; Devi, G; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Osada, T, Hsu, D, Hammond, S, Hobeika, A, Devi, G, Clay, TM, Lyerly, HK, and Morse, MA. "Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody." Br J Cancer 102.1 (January 5, 2010): 124-133.
PMID
19953093
Source
pubmed
Published In
British Journal of Cancer
Volume
102
Issue
1
Publish Date
2010
Start Page
124
End Page
133
DOI
10.1038/sj.bjc.6605364

Treatment-related toxicity and supportive care in metastatic colorectal cancer.

As survival of metastatic colorectal cancer (mCRC) increases, patients have more exposure to chemotherapy and related toxicity. The objective is to determine how toxicity patterns affect care. Via a population-based strategy, mCRC cases diagnosed between June 2003 and June 2006 were identified from one academic and nine community oncology practices in the southeastern United States. Demographic, disease, treatment, hospitalization, and toxicity data were abstracted by retrospective chart review, double-entered, and verified for accuracy. Of the 738 charts screened, 110 were eligible based upon preidentified inclusion criteria. As part of first-line chemotherapy, 87% received oxaliplatin, 12% received irinotecan, and 74% received bevacizumab. Gastrointestinal toxicity was the most common toxicity-related cause of drug discontinuation (16 of 61 events) and hospitalization (19 of 54 events). Both neurologic and hematologic toxicities were identified more frequently when oxaliplatin-containing regimens were administered (50% and 48%, respectively) than with irinotecan-containing regimens (10% and 24%, respectively). Dose reduction was most commonly associated with hematologic toxicity (22 of 55 events). Oxaliplatin and irinotecan required similar rates of antidiarrheal, antinausea, erythropoiesis-stimulating, and granulocyte-stimulating treatments. These data, obtained from a usual-practice setting, provide benchmarks to improve clinical practice.

Authors
Zafar, SY; Marcello, JE; Wheeler, JL; Rowe, KL; Morse, MA; Herndon, JE; Abernethy, AP
MLA Citation
Zafar, SY, Marcello, JE, Wheeler, JL, Rowe, KL, Morse, MA, Herndon, JE, and Abernethy, AP. "Treatment-related toxicity and supportive care in metastatic colorectal cancer." J Support Oncol 8.1 (January 2010): 15-20.
PMID
20235419
Source
pubmed
Published In
The Journal of Supportive Oncology
Volume
8
Issue
1
Publish Date
2010
Start Page
15
End Page
20

Colon cancer vaccines: An update

Despite advances in research and treatment modalities, colorectal cancer still accounts for around half a million deaths yearly worldwide. Traditional and even newer pharmaceutical therapeutic regimens are limited in terms of tolerance, efficacy and cross-resistance. Additional non-cross resistant therapies with non-overlapping toxicities are needed to improve the outcome for patients with colorectal cancer. Cancer vaccines, designed to activate immune effectors (T-cells and antibodies) to prevent recurrence or treat advanced cancers, have now demonstrated clinical benefit in prostate cancer and lymphoma. Because immune effector infiltration into colon tumours is associated with improved clinical outcome, vaccines intended to activate immune responses against colon cancer have generated significant interest. This review discusses data supportive of the immune responsiveness of colorectal cancer, as well as the current status of colon cancer vaccines under development including those based on whole tumour cells or lysates, peptide or protein antigens, anti-idiotype antibodies, viral vectors, and dendritic cells. We also discuss challenges to colon cancer vaccine development, such as tumour associated mechanisms for immune evasion, and how future strategies may address these challenges.

Authors
Merika, E; Saif, MW; Katz, A; Syrigos, C; Morse, M
MLA Citation
Merika, E, Saif, MW, Katz, A, Syrigos, C, and Morse, M. "Colon cancer vaccines: An update." In Vivo 24.5 (2010): 607-628.
PMID
20952724
Source
scival
Published In
In vivo (Athens, Greece)
Volume
24
Issue
5
Publish Date
2010
Start Page
607
End Page
628

Emerging Therapies: Introduction

Authors
Morse, MA; Llovet, JM
MLA Citation
Morse, MA, and Llovet, JM. Emerging Therapies: Introduction. December 9, 2009.
Source
scopus
Publish Date
2009
Start Page
347
End Page
351
DOI
10.1002/9781444317053

Colorectal Liver Metastases

Authors
Doan, PL; Vauthey, JN; Palavecino, M; Morse, MA
MLA Citation
Doan, PL, Vauthey, JN, Palavecino, M, and Morse, MA. "Colorectal Liver Metastases." Malignant Liver Tumors: Current and Emerging Therapies: Third Edition. December 9, 2009. 342-346.
Source
scopus
Publish Date
2009
Start Page
342
End Page
346
DOI
10.1002/9781444317053.ch29

Systemic Treatment of Hepatobiliary Tumors

Authors
Samaras, P; Morse, MA; Pestalozzi, BC
MLA Citation
Samaras, P, Morse, MA, and Pestalozzi, BC. "Systemic Treatment of Hepatobiliary Tumors." Malignant Liver Tumors: Current and Emerging Therapies: Third Edition. December 9, 2009. 107-121.
Source
scopus
Publish Date
2009
Start Page
107
End Page
121
DOI
10.1002/9781444317053.ch10

Novel Therapies Targeted at Signal Transduction in Liver Tumors

Authors
Huitzil-Melendez, FD; Abou-Alfa, GK; Morse, MA
MLA Citation
Huitzil-Melendez, FD, Abou-Alfa, GK, and Morse, MA. "Novel Therapies Targeted at Signal Transduction in Liver Tumors." Malignant Liver Tumors: Current and Emerging Therapies: Third Edition. December 9, 2009. 382-392.
Source
scopus
Publish Date
2009
Start Page
382
End Page
392
DOI
10.1002/9781444317053.ch32

Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors.

AIM: To determine the maximally tolerated dose (MTD), recommended phase II dose (RPTD) and toxicity profile of gemcitabine plus irinotecan combination. PATIENTS AND METHODS: Thirty-nine evaluable patients with advanced solid tumors were treated with gemcitabine (Gem) and irinotecan (Iri) on days 1, 8 and 15 of a 28-day cycle. Dose levels included Gem/Iri 700/50, 900/50, 900/75, 500/50 mg/m(2) respectively. Dose-limiting toxicity (DLT) was assessed during cycle one; toxicity evaluation was closely monitored throughout the course of treatment. Treatment continued until disease progression or unacceptable toxicity. RESULTS: DLTs primarily consisted of grade > or = 3 thrombocytopenia lasting > or = 4 days often accompanied by grade > or = 3 neutropenia. Other grade > or = 3 toxicities included vomiting, diarrhea, fatigue and elevated alkaline phosphatase. Three patients had a partial response. Stable disease as best response was seen in 16 patients, ranging from 2-18 months. CONCLUSION: The MTD/RPTD is gemcitabine 500 mg/m(2) plus irinotecan 50 mg/m(2) on days 1, 8 and 15 of a 28-day cycle. Given the toxicity profile and negative results of phase III studies, no further testing of this treatment combination is recommended.

Authors
Dugan, E; Truax, R; Meadows, KL; Blobe, GC; Morse, MA; Fernando, NH; Gockerman, JP; Petros, WP; Hurwitz, HI
MLA Citation
Dugan, E, Truax, R, Meadows, KL, Blobe, GC, Morse, MA, Fernando, NH, Gockerman, JP, Petros, WP, and Hurwitz, HI. "Phase I dose escalation study of gemcitabine plus irinotecan in advanced solid tumors." Anticancer Res 29.12 (December 2009): 5149-5153.
PMID
20044630
Source
pubmed
Published In
Anticancer research
Volume
29
Issue
12
Publish Date
2009
Start Page
5149
End Page
5153

Priming and activation of human ovarian and breast cancer-specific CD8+ T cells by polyvalent Listeria monocytogenes-based vaccines.

Immunotherapeutic vaccine is potentially an effective strategy to combat cancer. Essential components of an effective vaccine must include antigens that are processed by the major histocompatibility complex class I pathway, presented by the tumor major histocompatibility complex molecules, and an effective antigen delivery platform that is capable of breaking self-tolerance. In this study, we characterized a set of ovarian cancer-specific T-cell epitopes delivered by live-attenuated recombinant Listeria monocytogenes (Lm DeltaactADeltainlB) as a vaccine vector. We present data that peptide-specific T cells recognize the human monocytic cell line THP-1 infected with recombinant Lm DeltaactADeltainlB encoding the epitopes. Furthermore, we demonstrate that recombinant L. monocytogenes (Lm)-infected antigen-presenting cells can prime and expand epitope-specific CD8 T cells in vitro and such CD8 T cells recognize not only peptide-loaded targets but also ovarian and breast tumor cells presenting endogenous epitopes. Finally, peptide-specific T cells generated using peripheral blood mononuclear cell from ovarian cancer patients recognize target cells infected with recombinant Lm DeltaactADeltainlB encoding the epitopes. Our results demonstrate that live-attenuated recombinant Lm can be used effectively as a vehicle to deliver cancer peptide antigens singly or as a multiepitope construct. Thus, the use of recombinant live-attenuated Lm strains encoding endogenously processed and presented tumor epitopes/antigens represents an attractive strategy for active cancer immunotherapy in a clinical setting.

Authors
Sinnathamby, G; Lauer, P; Zerfass, J; Hanson, B; Karabudak, A; Krakover, J; Secord, AA; Clay, TM; Morse, MA; Dubensky, TW; Brockstedt, DG; Philip, R; Giedlin, M
MLA Citation
Sinnathamby, G, Lauer, P, Zerfass, J, Hanson, B, Karabudak, A, Krakover, J, Secord, AA, Clay, TM, Morse, MA, Dubensky, TW, Brockstedt, DG, Philip, R, and Giedlin, M. "Priming and activation of human ovarian and breast cancer-specific CD8+ T cells by polyvalent Listeria monocytogenes-based vaccines." J Immunother 32.8 (October 2009): 856-869.
PMID
19752748
Source
pubmed
Published In
Journal of Immunotherapy
Volume
32
Issue
8
Publish Date
2009
Start Page
856
End Page
869
DOI
10.1097/CJI.0b013e3181b0b125

Cellular uptake of neutral phosphorodiamidate morpholino oligomers.

Phosphorodiamidate morpholino oligomers (PMO), which have a neutral chemistry, are extensively being used as tools for selective inhibition of gene expression in cell culture models and are currently in human clinical trials. Unlike phosphorothioates (PS ODN) and other charged oligonucleotides, little is known about the uptake characteristics of neutral oligomers. The purpose of this study was to understand the kinetics of PMO transport in cells and correlate with antisense activity. In contrast to primary cells and some transformed cell lines which were uptake permissive, established cancer cell lines showed very poor uptake with an occasional diffuse intracellular pattern. Differential PMO uptake was also observed in immune cells, with dendritic cells and monocytes showing highest uptake compared to T and B cells. In addition, PMO localization was observed to be heterogeneous within a population of uptake permissive cells. Unassisted PMO delivery targeting specific genes was correlated with functional antisense efficacy in experiments showing correction of pre-mRNA missplicing and inhibition of target enzyme activity in cells in culture. PMO internalization in uptake-permissive cells was identified to be specific, saturable, and energy-dependent, suggesting a receptor mediated uptake mechanism. Understanding PMO transport should facilitate the design of more effective synthetic antisense oligomers as therapeutic agents.

Authors
Iversen, PL; Aird, KM; Wu, R; Morse, MM; Devi, GR
MLA Citation
Iversen, PL, Aird, KM, Wu, R, Morse, MM, and Devi, GR. "Cellular uptake of neutral phosphorodiamidate morpholino oligomers." Curr Pharm Biotechnol 10.6 (September 2009): 579-588.
PMID
19619124
Source
pubmed
Published In
Current Pharmaceutical Biotechnology
Volume
10
Issue
6
Publish Date
2009
Start Page
579
End Page
588

Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity.

Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in pre-clinical models, but have muted responses in human trials because of widespread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5-specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data show that [E1-, E2b-]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5-specific immunity, in contrast to [E1-] vectors. These pre-clinical studies with E1 and E2b-deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor, and that clinical trials to evaluate their performance are warranted.

Authors
Osada, T; Yang, XY; Hartman, ZC; Glass, O; Hodges, BL; Niedzwiecki, D; Morse, MA; Lyerly, HK; Amalfitano, A; Clay, TM
MLA Citation
Osada, T, Yang, XY, Hartman, ZC, Glass, O, Hodges, BL, Niedzwiecki, D, Morse, MA, Lyerly, HK, Amalfitano, A, and Clay, TM. "Optimization of vaccine responses with an E1, E2b and E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity." Cancer Gene Ther 16.9 (September 2009): 673-682.
PMID
19229288
Source
pubmed
Published In
Cancer Gene Therapy
Volume
16
Issue
9
Publish Date
2009
Start Page
673
End Page
682
DOI
10.1038/cgt.2009.17

Longitudinal patterns of chemotherapy use in metastatic colorectal cancer.

Multiple agents and combination therapies available to patients with advanced colorectal cancer have significantly improved survival and provided an opportunity for individualization of care, allowing clinicians and patients to prioritize risks and benefits of comparable regimens.

Authors
Zafar, SY; Marcello, JE; Wheeler, JL; Rowe, KL; Morse, MA; Herndon, JE; Abernethy, AP
MLA Citation
Zafar, SY, Marcello, JE, Wheeler, JL, Rowe, KL, Morse, MA, Herndon, JE, and Abernethy, AP. "Longitudinal patterns of chemotherapy use in metastatic colorectal cancer." J Oncol Pract 5.5 (September 2009): 228-233.
PMID
20856733
Source
pubmed
Published In
Journal of Oncology Practice
Volume
5
Issue
5
Publish Date
2009
Start Page
228
End Page
233
DOI
10.1200/JOP.091010

Physiology and therapeutics of vascular endothelial growth factor in tumor immunosuppression.

Vascular endothelial growth factor (VEGF), known as a primary mediator of tumor-induced angiogenesis, is now understood to have a role in tumor-associated immunosuppression. Initially, VEGF was identified to alter the growth and maturation of the immature granulocyte-macrophage progenitors, and more recently it has been noted that it prevents dendritic cell (DC) precursors from developing into mature, antigen-presenting DC. VEGF is associated with recruitment of macrophages to the tumor stroma and VEGF inhibition of myeloid progenitor maturation is associated with the development tumor associated macrophages (TAM) which possess immunosuppressive capacity as well. Therapies intended to inhibit VEGF or VEGF receptors have demonstrated improved anti-tumor immunity and enhanced responses to cancer vaccines.

Authors
Johnson, B; Osada, T; Clay, T; Lyerly, H; Morse, M
MLA Citation
Johnson, B, Osada, T, Clay, T, Lyerly, H, and Morse, M. "Physiology and therapeutics of vascular endothelial growth factor in tumor immunosuppression." Curr Mol Med 9.6 (August 2009): 702-707. (Review)
PMID
19689297
Source
pubmed
Published In
Current molecular medicine
Volume
9
Issue
6
Publish Date
2009
Start Page
702
End Page
707

Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma.

BACKGROUND: To explore the biological activity of EMD 273063 (hu14.18-IL2), a humanized anti-GD2 monoclonal antibody fused to interleukin-2 (IL2), in patients with unresectable, stage IV cutaneous melanoma as measured by induction of immune activation at the tumor site and in peripheral blood. METHODS: Nine patients were treated with 4 mg/m2 per day of EMD 273063 given as a 4-h intravenous infusion on days 1, 2, and 3 every four weeks (one cycle). Peripheral blood was analyzed for T cell and natural killer cell phenotype and frequency, as well as levels of soluble IL2 receptor (sIL2R), IL10, IL6, tumor necrosis factor alpha and neopterin. Biopsies of tumor metastasis were performed prior to therapy and at day 10 of the first 2 cycles to study lymphocyte accumulation by immunohistochemistry. RESULTS: Treatment was generally well tolerated and there were no study drug-related grade 4 adverse events. Grade 3 events were mainly those associated with IL2, most commonly rigors (3 patients) and pyrexia (2 patients). Best response on therapy was stable disease in 2 patients. There were no objective tumor regressions by standard response criteria. Systemic immune activation was demonstrated by increases in serum levels of sIL2R, IL10, and neopterin. There was evidence of increased tumor infiltration by T cells, but not NK cells, in most post-dosing biopsies, suggesting recruitment of immune cells to the tumor site. CONCLUSION: EMD 273063 demonstrated biologic activity with increased immune-related cytokines and intratumoral changes in some patients consistent with the suspected mechanism of action of this immunocytokine.

Authors
Ribas, A; Kirkwood, JM; Atkins, MB; Whiteside, TL; Gooding, W; Kovar, A; Gillies, SD; Kashala, O; Morse, MA
MLA Citation
Ribas, A, Kirkwood, JM, Atkins, MB, Whiteside, TL, Gooding, W, Kovar, A, Gillies, SD, Kashala, O, and Morse, MA. "Phase I/II open-label study of the biologic effects of the interleukin-2 immunocytokine EMD 273063 (hu14.18-IL2) in patients with metastatic malignant melanoma. (Published online)" J Transl Med 7 (July 29, 2009): 68-.
PMID
19640287
Source
pubmed
Published In
Journal of Translational Medicine
Volume
7
Publish Date
2009
Start Page
68
DOI
10.1186/1479-5876-7-68

Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis.

The optimal timing of chemotherapy relative to resection of synchronous colorectal liver metastases (SCRLM) is not known. The objective of this retrospective multi-institutional study was to assess the influence of chemotherapy administered before and after hepatic resection on long-term outcomes among patients with initially resectable SCRLM treated from 1995 to 2005. Clinicopathologic data, treatments, and long-term outcomes from patients with initially resectable SCRLM who underwent partial hepatectomy at three hepatobiliary centers were reviewed. Four hundred ninety-nine consecutive patients underwent resection; 297 (59.5%) and 264 (52.9%) were treated with chemotherapy before and after resection. Chemotherapy strategies included pre-hepatectomy alone (n = 148, 24.7%), post-hepatectomy alone (n = 115, 23.0%), perioperative (n = 149, 29.0%), and no chemotherapy (n = 87, 17.4%). Male gender (p = 0.0029, HR = 1.41 [1.12-1.77]), node-positive primary tumor (p = 0.0046, HR = 1.40 [1.11-1.77]), four or more SCRLM (p = 0.0005, HR = 1.65 [1.24-2.18]), and post-hepatectomy chemotherapy treatment for 6 months or longer (p = 0.039, HR = 0.75 [0.57-0.99]) were associated with recurrence-free survival after discovery of SCRLM. Carcinoembryonic antigen >200 ng/ml (p = 0.0003, HR = 2.33 [1.48-3.69]), extrahepatic metastatic disease (p = 0.0025, HR = 2.34 [1.35-4.05]), four or more SCRLM (p = 0.033, HR = 1.43 [1.03-2.00]), and post-hepatectomy chemotherapy treatment for 2 months or longer (p < 0.0001, HR = 0.59 [0.45-0.76]) were associated with overall survival. Pre-hepatectomy chemotherapy was not associated with recurrence-free or overall survival. Patients treated with perioperative chemotherapy had similar outcomes as patients treated with post-hepatectomy chemotherapy only. We conclude that chemotherapy administered after but not before resection of SCRLM was associated with improved recurrence-free and overall survival. However, prospective randomized trials are needed to determine the optimal timing of chemotherapy.

Authors
Reddy, SK; Zorzi, D; Lum, YW; Barbas, AS; Pawlik, TM; Ribero, D; Abdalla, EK; Choti, MA; Kemp, C; Vauthey, J-N; Morse, MA; White, RR; Clary, BM
MLA Citation
Reddy, SK, Zorzi, D, Lum, YW, Barbas, AS, Pawlik, TM, Ribero, D, Abdalla, EK, Choti, MA, Kemp, C, Vauthey, J-N, Morse, MA, White, RR, and Clary, BM. "Timing of multimodality therapy for resectable synchronous colorectal liver metastases: a retrospective multi-institutional analysis." Ann Surg Oncol 16.7 (July 2009): 1809-1819.
PMID
18979139
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
16
Issue
7
Publish Date
2009
Start Page
1809
End Page
1819
DOI
10.1245/s10434-008-0181-y

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Authors
Cohen, SJ; Punt, CJ; Iannotti, N; Saidman, BH; Sabbath, KD; Gabrail, NY; Picus, J; Morse, MA; Mitchell, E; Miller, MC; Doyle, GV; Tissing, H; Terstappen, LW; Meropol, NJ
MLA Citation
Cohen, SJ, Punt, CJ, Iannotti, N, Saidman, BH, Sabbath, KD, Gabrail, NY, Picus, J, Morse, MA, Mitchell, E, Miller, MC, Doyle, GV, Tissing, H, Terstappen, LW, and Meropol, NJ. "Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer." Ann Oncol 20.7 (July 2009): 1223-1229.
PMID
19282466
Source
pubmed
Published In
Annals of Oncology
Volume
20
Issue
7
Publish Date
2009
Start Page
1223
End Page
1229
DOI
10.1093/annonc/mdn786

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)

Authors
Bullock, KE; Hurwitz, HI; Uronis, HE; Morse, MA; Blobe, GC; Hsu, SD; Zafar, SY; Nixon, AB; Howard, LA; Bendell, JC
MLA Citation
Bullock, KE, Hurwitz, HI, Uronis, HE, Morse, MA, Blobe, GC, Hsu, SD, Zafar, SY, Nixon, AB, Howard, LA, and Bendell, JC. "Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC).

4080 Background: For patients (pts) with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC.25 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance.At this time, 19 pts (10M: 9F) are evaluable for toxicity; 17 for efficacy. Median age 57 years (range 35-78). Median number prior regimens 3. All pts had prior B exposure; 17 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia. Grade 3 AE related to treatment were bowel perforation/fistula, (n=2), hyperglycemia (3), hypokalemia (3), hypertension (2), fatigue (1), alk phos elevation (1; lab only), hypoalbuminemia (1), and volume depletion (1). Other events of interest were: Gr1-2 mucositis (n=10), Gr1 hyperlipidemia (11). Of 17 pts evaluable for response, 4 pts had SD as best response (median 24 wks, range 17-31+ wks); there were 3 minor responses in pts who had progressed on B (median 16 wks, range 16-27 wks). No CR or PR were seen. Biomarker data is pending.B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. Patient accrual is continuing and updated data will be presented. [Table: see text].

Authors
Bullock, KE; Hurwitz, HI; Uronis, HE; Morse, MA; Blobe, GC; Hsu, SD; Zafar, SY; Nixon, AB; Howard, LA; Bendell, JC
MLA Citation
Bullock, KE, Hurwitz, HI, Uronis, HE, Morse, MA, Blobe, GC, Hsu, SD, Zafar, SY, Nixon, AB, Howard, LA, and Bendell, JC. "Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 4080-.
PMID
27961646
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
4080

Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine.

PURPOSE: Wilms' tumor protein (WT1) is overexpressed in most leukemias and many solid tumors and is a promising target for tumor immunotherapy. WT1 peptide-based cancer vaccines have been reported but have limited application due to HLA restriction of the peptides. We sought to vaccinate using adenoviral (Ad) vectors encoding tumor-associated antigens such as WT1 that can stimulate tumor-associated antigen-specific immunity across a broad array of HLA types and multiple class I and class II epitopes. EXPERIMENTAL DESIGN: We developed a novel Ad vector encoding a truncated version of WT1 (Ad-tWT1) lacking the highly conserved COOH terminus zinc finger domains and tested its ability to stimulate WT1-specific immune responses and antitumor immunity in two murine models of WT1-expressing tumors. RESULTS: Despite encoding a transcription factor, we found that Ad-tWT1-transduced murine and human dendritic cells showed cytoplasmic expression of the truncated WT1 protein. In addition, vaccination of C57BL/6 mice with Ad-tWT1 generated WT1-specific cell-mediated and humoral immune responses and conferred protection against challenge with the leukemia cell line, mWT1-C1498. Moreover, in a tumor therapy model, Ad-tWT1 vaccination of TRAMP-C2 tumor-bearing mice significantly suppressed tumor growth. CONCLUSIONS: This is the first report of a WT1-encoding Ad vector that is capable of inducing effective immunity against WT1-expressing malignancies. Based on these findings, Ad-tWT1 warrants investigation in human clinical trials to evaluate its applications as a vaccine for patients with WT1-expressing cancers.

Authors
Osada, T; Woo, CY; McKinney, M; Yang, XY; Lei, G; Labreche, HG; Hartman, ZC; Niedzwiecki, D; Chao, N; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Osada, T, Woo, CY, McKinney, M, Yang, XY, Lei, G, Labreche, HG, Hartman, ZC, Niedzwiecki, D, Chao, N, Amalfitano, A, Morse, MA, Lyerly, HK, and Clay, TM. "Induction of Wilms' tumor protein (WT1)-specific antitumor immunity using a truncated WT1-expressing adenovirus vaccine." Clin Cancer Res 15.8 (April 15, 2009): 2789-2796.
PMID
19351755
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
8
Publish Date
2009
Start Page
2789
End Page
2796
DOI
10.1158/1078-0432.CCR-08-2589

Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer.

BACKGROUND: Vaccines for pancreatic cancer have been challenged by a number of factors, especially the immunosuppressive microenvironment within the tumor that allows for escape from immune surveillance. OBJECTIVE/METHODS: We sought to identify results that define mechanisms of pancreatic-cancer-associated immunosuppression and strategies that might be useful to overcome them thereby resulting in effective immune responses to cancer vaccines capable of deleting pancreatic cancer cells. RESULTS/CONCLUSION: Immunosuppressive tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg) reside in tumors, and their products along with tumor derived products (such as VEGF, TGFbeta and IL-10), create a microenvironment that counters immune activation and attack. Immunotherapy with cancer vaccines must include strategies to modulate these immunosuppressive cell types and tumor byproducts. Clinical trials are beginning to test these strategies.

Authors
Morse, MA; Hall, JR; Plate, JM
MLA Citation
Morse, MA, Hall, JR, and Plate, JM. "Countering tumor-induced immunosuppression during immunotherapy for pancreatic cancer." Expert Opin Biol Ther 9.3 (March 2009): 331-339. (Review)
PMID
19216622
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
9
Issue
3
Publish Date
2009
Start Page
331
End Page
339
DOI
10.1517/14712590802715756

Turning lemons into lemonade: learning from negative studies in cancer immunotherapy.

Authors
Morse, MA; Whelan, M
MLA Citation
Morse, MA, and Whelan, M. "Turning lemons into lemonade: learning from negative studies in cancer immunotherapy." Curr Opin Mol Ther 11.1 (February 2009): 10-12.
PMID
19169954
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
11
Issue
1
Publish Date
2009
Start Page
10
End Page
12

Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma.

PURPOSE: Extrahepatic cholangiocarcinoma is a rare malignancy. Despite radical resection, survival remains poor, with high rates of local and distant failure. To clarify the role of radiotherapy with chemotherapy, we performed a retrospective analysis of resected patients who had undergone chemoradiotherapy. METHODS AND MATERIALS: A total of 45 patients (13 with proximal and 32 with distal disease) underwent resection plus radiotherapy (median dose, 50.4 Gy). All but 1 patient received concurrent fluoropyrimidine-based chemotherapy. The median follow-up was 30 months for all patients and 40 months for survivors. RESULTS: Of the 45 patients, 33 underwent adjuvant radiotherapy, and 12 were treated neoadjuvantly. The 5-year actuarial overall survival, disease-free survival, metastasis-free survival, and locoregional control rates were 33%, 37%, 42%, and 78%, respectively. The median survival was 34 months. No patient died perioperatively. Patient age

Authors
Nelson, JW; Ghafoori, AP; Willett, CG; Tyler, DS; Pappas, TN; Clary, BM; Hurwitz, HI; Bendell, JC; Morse, MA; Clough, RW; Czito, BG
MLA Citation
Nelson, JW, Ghafoori, AP, Willett, CG, Tyler, DS, Pappas, TN, Clary, BM, Hurwitz, HI, Bendell, JC, Morse, MA, Clough, RW, and Czito, BG. "Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma." Int J Radiat Oncol Biol Phys 73.1 (January 1, 2009): 148-153.
PMID
18805651
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
73
Issue
1
Publish Date
2009
Start Page
148
End Page
153
DOI
10.1016/j.ijrobp.2008.07.008

Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study.

BACKGROUND: Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM. METHODS: Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed. RESULTS: From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis. CONCLUSIONS: The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.

Authors
Reddy, SK; Broadwater, G; Niedzwiecki, D; Barbas, AS; Hurwitz, HI; Bendell, JC; Morse, MA; Clary, BM
MLA Citation
Reddy, SK, Broadwater, G, Niedzwiecki, D, Barbas, AS, Hurwitz, HI, Bendell, JC, Morse, MA, and Clary, BM. "Multiagent chemotherapy for isolated colorectal liver metastases: a single-centered retrospective study." J Gastrointest Surg 13.1 (January 2009): 74-84.
PMID
18685900
Source
pubmed
Published In
Journal of Gastrointestinal Surgery
Volume
13
Issue
1
Publish Date
2009
Start Page
74
End Page
84
DOI
10.1007/s11605-008-0617-5

A phase II study of long-acting octeotride in patients with advanced hepatocellular carcinoma and CLIP score of 3 or higher

Background: Studies of octreotide in hepatocellular carcinoma have yielded conflicting results. Since past studies have excluded patients with highly advanced disease and given the fact that octreotide offers several potential physiologic benefits in patients with advanced cirrhosis, such as improving renal physiology and decreasing portal venous pressure, we designed a trial to examine the survival of patients with both advanced HCC and advanced cirrhosis as defined by a CLIP score of 3 or higher. Patients and Methods: The study was designed as a phase-II, multicenter trial, enrolling patients with advanced HCC in three tertiary care academic centers in the United States. The primary objective was to verify whether long-acting octreotide will extend median survival from 5 months to 8.75 months for patients with CLIP scores of 3 or higher, representing a 75% increase in median survival time. Secondary objectives included assessing safety and tolerability in this patient population. Results: Twenty-two patients were enrolled from 2003 to 2005. The mean age was 66, with the majority of patients being men. The median CLIP score was 4 with a median KPS of 80%. Ten of 22 patients died without evidence of progression of HCC. The median TTP was 5.7 months (95% confidence interval [CI], 2.8-10.7). The median PFS time was approximately 3 months (95% CI, 1.7-5.7). The median OS time was 4.5 months (95% CI, 2.3-8) and therefore did not meet the established primary end point. Six of 22 patients achieved an OS of greater than 10 months. One patient experienced a radiographic partial response. Conclusions: Long-acting octreotide was not associated with a survival benefit in patients with significant liver disease related to HCC. The identification of one patient with disease regression and a subgroup of patients with significantly greater survival underscores the need to gain a better understanding of the role of somatostatin receptors on HCC cells before further clinical testing of this drug in HCC patients. © 2009 by International Society of Gastrointestinal Oncology.

Authors
Shah, U; O'Neil, B; Allen, J; Goldberg, RM; Bernard, S; Moore, D; Venook, AP; Morse, MM
MLA Citation
Shah, U, O'Neil, B, Allen, J, Goldberg, RM, Bernard, S, Moore, D, Venook, AP, and Morse, MM. "A phase II study of long-acting octeotride in patients with advanced hepatocellular carcinoma and CLIP score of 3 or higher." Gastrointestinal Cancer Research 3.2 (2009): 45-48.
Source
scival
Published In
Gastrointestinal Cancer Research
Volume
3
Issue
2
Publish Date
2009
Start Page
45
End Page
48

Immune Cells and the Tumor Microenvironment

Authors
Hsu, DS; Morse, M; Clay, T; Devi, G; Lyerly, HK
MLA Citation
Hsu, DS, Morse, M, Clay, T, Devi, G, and Lyerly, HK. "Immune Cells and the Tumor Microenvironment." 2009. 818-829.
Source
scival
Publish Date
2009
Start Page
818
End Page
829
DOI
10.1016/B978-0-12-369420-1.00068-8

Status of colon cancer vaccines. [An interview with Michael Morse by H&O].

Authors
Morse, MA
MLA Citation
Morse, MA. "Status of colon cancer vaccines. [An interview with Michael Morse by H&O]." Clin Adv Hematol Oncol 6.11 (November 2008): 789-794. (Interview)
PMID
19194360
Source
pubmed
Published In
Clinical advances in hematology & oncology : H&O
Volume
6
Issue
11
Publish Date
2008
Start Page
789
End Page
794

Advances in immunotherapy for colorectal malignancies

Authors
McKinney, M; Morse, MA
MLA Citation
McKinney, M, and Morse, MA. "Advances in immunotherapy for colorectal malignancies." Current Colorectal Cancer Reports 4.4 (October 2008): 177-183.
Source
crossref
Published In
Current Colorectal Cancer Reports
Volume
4
Issue
4
Publish Date
2008
Start Page
177
End Page
183
DOI
10.1007/s11888-008-0029-7

Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines.

CD4(+)CD25(high)FoxP3(+) regulatory T (Treg) cells limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. In preclinical and clinical studies, we assessed the immune consequences of FoxP3(+) Treg-cell depletion in patients with advanced malignancies. We demonstrated that a CD25(high) targeting immunotoxin (denileukin diftitox) depleted FoxP3(+) Treg cells, decreased Treg-cell function, and enhanced antigen-specific T-cell responses in vitro. We then attempted to enhance antitumor immune responses in patients with carcinoembryonic antigen (CEA)-expressing malignancies by Treg-cell depletion. In a pilot study (n = 15), denileukin diftitox, given as a single dose or repeated dosing, was followed by immunizations with dendritic cells modified with the fowlpox vector rF-CEA(6D)-TRICOM. By flow cytometric analysis, we report the first direct evidence that circulating CD4(+)CD25(high)FoxP3(+) Treg cells are depleted after multiple doses of denileukin diftitox. Earlier induction of, and overall greater exposure to, the T-cell response to CEA was observed in the multiple-dose group, but not the single-dose group. These results indicate the potential for combining Treg-cell depletion with anticancer vaccines to enhance tumor antigen-specific immune responses and the need to explore dose and schedule of Treg depletion strategies in optimizing vaccine efforts.

Authors
Morse, MA; Hobeika, AC; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Hobeika, AC, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Clay, TM. "Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines." Blood 112.3 (August 1, 2008): 610-618.
PMID
18519811
Source
pubmed
Published In
Blood
Volume
112
Issue
3
Publish Date
2008
Start Page
610
End Page
618
DOI
10.1182/blood-2008-01-135319

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients.

Impairment of dendritic cells (DC), the most effective activators of anticancer immune responses, is one mechanism for defective antitumor immunity, but the causes of DC impairment are incompletely understood. We evaluated the association of impaired DC differentiation with angiogenesis-associated molecules D-dimer, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor (PAI-1) in peripheral blood from 41 patients with lung, breast, and colorectal carcinoma. Subsequently, we studied the effect of administration of the anti-VEGF antibody (bevacizumab) on DC maturation and function in vivo. Compared with healthy volunteers, cancer patients had a bias toward the immunoregulatory DC2, had deficits in DC maturation after overnight in vitro culture, and had a significant increase in immature myeloid cell progenitors of DC (0.50 +/- 0.31% vs. 0.32 +/- 0.16% of peripheral blood mononuclear cells, respectively, P = 0.011). A positive correlation was found between the percentage of DC2 and PAI-1 (R = 0.50) and between immature myeloid cells and VEGF (R = 0.52). Bevacizumab administration to cancer patients was associated with a decrease in the accumulation of immature progenitor cells (0.39 +/- 0.30% vs. 0.27 +/- 0.24%, P = 0.012) and induced a modest increase in the DC population in peripheral blood (0.47 +/- 0.23% vs. 0.53 +/- 0.30%). Moreover, anti-VEGF antibody treatment enhanced allo-stimulatory capacity of DC and T cell proliferation against recall antigens. These data suggest that DC differentiation is negatively associated with VEGF levels and may be one explanation for impaired anticancer immunity, especially in patients with advanced malignancies.

Authors
Osada, T; Chong, G; Tansik, R; Hong, T; Spector, N; Kumar, R; Hurwitz, HI; Dev, I; Nixon, AB; Lyerly, HK; Clay, T; Morse, MA
MLA Citation
Osada, T, Chong, G, Tansik, R, Hong, T, Spector, N, Kumar, R, Hurwitz, HI, Dev, I, Nixon, AB, Lyerly, HK, Clay, T, and Morse, MA. "The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients." Cancer Immunol Immunother 57.8 (August 2008): 1115-1124.
PMID
18193223
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
57
Issue
8
Publish Date
2008
Start Page
1115
End Page
1124
DOI
10.1007/s00262-007-0441-x

E/Tablets to collect research-quality, patient-reported data.

17528 Background: Programmed, wireless, notebook-and-pen style, computers ("e/Tablets") can collect review of systems data at the point of care, for use in the clinic visit. Can e/Tablets deployed in outpatient oncology clinics be used to collect research survey data that are comparable to paper-based data? METHODS: We used PACE e/Tablets (SOS, Inc.) to administer the disease-specific Functional Assessment of Cancer Therapy (FACT), MD Anderson Symptom Inventory (MDASI), and FACT-GOG-Neurotoxicity (NTX) scales. Participants were 113 gastrointestinal (GI) cancer patients in Duke GI Oncology Clinic. At each of 4 visits in 6 months, participants completed all surveys in electronic format and 1 survey on paper. Subscales (electronic vs. paper) were compared using paired t-tests. Patients completed an electronic satisfaction survey. RESULTS: Mean age, 57 (SD 11); 67% male; 80% Caucasian; 47% no college degree; 67% metastatic cancer. Patients strongly supported e/Tablets: easy to read (97%), easy to respond to questions (97%), weight of computer comfortable (92%). Patients reported e/Tablets to be helpful for reporting symptoms (82%), and would recommend them to other patients (88%). After Bonferonni corrections (0.05/10=0.005), survey subscale scores for paper and electronic were similar except for the NTX scale. CONCLUSIONS: Patients are satisfied with e/Tablets to collect survey data. Preliminary results show that e/Tablets furnish comparable data to those collected by paper questionnaires on nearly all subscales tested. These results in GI cancers support our previous breast cancer study results, suggesting that e/Tablets offer a valid, feasible method for collecting research-quality, clinically relevant data from patients in outpatient academic oncology. [Table: see text] [Table: see text].

Authors
Uronis, HE; Herndon, JE; Coan, A; Bronson, K; Wheeler, J; Lyerly, HK; Morse, MA; Abernethy, AP
MLA Citation
Uronis, HE, Herndon, JE, Coan, A, Bronson, K, Wheeler, J, Lyerly, HK, Morse, MA, and Abernethy, AP. "E/Tablets to collect research-quality, patient-reported data." J Clin Oncol 26.15_suppl (May 20, 2008): 17528-.
PMID
27950469
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
17528

Longitudinal patterns of chemotherapy (CT) use in metastatic colorectal cancer (mCRC).

15082 Background: As mCRC survival increases beyond 2 years, patients (pts) have more exposure to multiple CT regimens. Insight into patterns of care in mCRC treatment is crucial to understanding physician and patient decision-making priorities. METHODS: Using a population-based strategy, we identified CRC cases from 1 academic and 9 community oncology practices in the southeastern US with mCRC diagnosed between 6/03-6/06, and treatment with an oxaliplatin- (O) or irinotecan- (IR) based CT regimen during that period. Demographic, disease, treatment, and toxicity data were abstracted by retrospective chart review, double-entered and verified for accuracy. RESULTS: Of 743 charts screened, 110 were eligible: mean age 57.9 (SD 12.2), 74% Stage IV at diagnosis, 39% male, 53% white, 26% black, and 13% ≥70 years. As part of 1st-line mCRC CT, 100% of pts received regimens containing 5-fluorouracil (5-FU), 87% (95% CI 81-93%) received O, 12% (95% CI 6-18%) received IR, and 74% (95% CI 66-82%) received bevacizumab (B). The proportions of pts receiving subsequent lines of CT were: 2nd-line 48% (n=53), 3rd-line 26% (n=29), 4th-line 14% (n=15), and 5th-line 5% (n=5). From 1st to 3rd line, the use of O and B decreased, while IR use increased (see Table ). Therapy was discontinued 29% of the time for disease progression (PD) and 19% of the time for toxicity; 27% had no reason documented. 22% (n=25/114) of O- and 34% (n=20/59) of IR-containing regimens were discontinued for PD. 19% (n=21/114) of O- and 20% (n=12/59) of IR-containing regimens were discontinued for toxicity. CONCLUSIONS: Along with 5-FU, O and B were most commonly used in 1st-line for mCRC. Use of O decreased and IR increased as treatment progressed beyond 1st-line. [Table: see text] [Table: see text].

Authors
Herndon, JE; Zafar, Y; Marcello, J; Wheeler, J; Rowe, K; Morse, MA; Abernethy, AP
MLA Citation
Herndon, JE, Zafar, Y, Marcello, J, Wheeler, J, Rowe, K, Morse, MA, and Abernethy, AP. "Longitudinal patterns of chemotherapy (CT) use in metastatic colorectal cancer (mCRC)." J Clin Oncol 26.15_suppl (May 20, 2008): 15082-.
PMID
27950330
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
15082

Initial results of a phase II study of oxaliplatin (OX), capecitabine (CAP), bevacizumab (BV), and cetuximab (CET) in the treatment of metastatic colorectal cancer (mCRC).

4063 Background: FOLFOX/XELOX + BV are standard 1st line regimens for the treatment of mCRC. Based upon the activity of CET in mCRC, promising data with the XELOX-A regimen, and preclinical and early clinical data suggesting benefit from simultaneous targeting of the VEGF and EGFR pathways, we evaluated the safety and efficacy adding CET to the XELOX-A regimen. METHODS: Pts with untreated mCRC received XELOX-AE: OX 130 mg/m(2) d1, CAP 850 mg/m(2) BID d1-14, BV 7.5 mg/kg d1, and CET 250 mg/m(2) d1, 8, and 15 (loading dose CET = 400 mg/m(2)). Cycles were repeated every 3 weeks. Blood was collected for markers of response and resistance. RESULTS: 29 pts have mature data for toxicity; 24 for efficacy. Median age 56 (range 33-76). Grade 3/4 adverse events which occurred in > 10 % of patients were: diarrhea (7/29 G3) and skin rash (9/29 G3). Other events of interest were: neuropathy (21/29, 2 G3), hypomagnesemia (15/29, 3 G 3) proteinuria (3 G2), HTN (1 G1), hand-foot syndrome (1 G1, 4 G2). 17/29 pts required dose modifications (16 OX, 9 CET, 11 CAP). There were 24 pts evaluable for response, 1 CR, 10 PR, 12 SD, and 1 PD (RR=45.8%; 95% CI: 27.0%-64.6%). Median progression free survival was 10.6 months (95% CI: 7.4-16.2). Median time to progression (TTP) was 14.0 months (95% CI: 7.4-16.2). CONCLUSIONS: XELOX-AE is an active regimen in the first line treatment of metastatic colorectal cancer. However, initial RR and PFS data approximate that of treatment with CAP, OX, and BEV alone, with an increase in toxicity, mainly skin rash, hypomagnesemia, and possibly diarrhea. Patient accrual is continuing. Updated data will be presented. [Table: see text].

Authors
Bendell, JC; Uronis, HE; Morse, MA; Blobe, G; Aklilu, M; Nixon, A; Niedzweicki, D; Honeycutt, W; Howard, L; Hurwitz, H
MLA Citation
Bendell, JC, Uronis, HE, Morse, MA, Blobe, G, Aklilu, M, Nixon, A, Niedzweicki, D, Honeycutt, W, Howard, L, and Hurwitz, H. "Initial results of a phase II study of oxaliplatin (OX), capecitabine (CAP), bevacizumab (BV), and cetuximab (CET) in the treatment of metastatic colorectal cancer (mCRC)." J Clin Oncol 26.15_suppl (May 20, 2008): 4063-.
PMID
27949512
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4063

Treatment-related toxicity and supportive care in metastatic colorectal cancer (mCRC).

15087 Background: As mCRC survival increases, patients have more exposure to chemotherapy (CT) and related toxicity. How do toxicity patterns affect care? METHODS: Using a population-based strategy, we identified CRC cases from 1 academic and 9 community oncology practices with mCRC diagnosed between 6/03-6/06, and initial mCRC treatment with an oxaliplatin- (O) or irinotecan- (IR) based CT. Demographic, disease, treatment, and toxicity data were abstracted by retrospective chart review, double-entered and verified. Hospitalization, drug discontinuation, and drug reduction events were per clinician report; one case could have had multiple events. RESULTS: Of 743 charts screened, 110 were eligible based upon pre-identified inclusion criteria: mean age 58 (SD 12), 74% Stage IV at diagnosis, 39% male, 53% white, 26% black, and 13% ≥70 years. As part of 1st-line mCRC CT, 87% received O [all FOLFOX], 12% received IR [all FOLFIRI], and 74% received bevacizumab (B). When treated with 1st-line O, 50% did not receive 2nd-line CT; when treated with 1st-line IR, 38% did not receive 2nd-line CT. Gastrointestinal (GI) toxicity was documented across 52% of all regimens (57% O, 59% IR), and was the most common toxicity-related cause of drug discontinuation (16 of 61 events) and hospitalization (19 of 54 events). Dose reduction was most commonly due to hematologic toxicity (22 of 55 events). When treated with O (n=114 total treatment lines), dose reduction was due to hematologic toxicity (16%) and drug discontinuation due to neurotoxicity (8%). When treated with IR (n=59 total treatment lines), dose reduction and discontinuation were primarily due to GI toxicity, 12% and 10% respectively. O and IR required similar rates of anti-diarrheal (O 22%, IR 20%), anti-nausea (O 20%, IR 26%), erythropoiesis- (O 19%, IR 9%), and granulocyte-stimulating (O 25%, IR 11%,) treatments (all p's NS). CONCLUSIONS: In this mCRC sample, GI toxicity was the most common driver of toxicity-related drug discontinuation and hospitalization; dose reduction was most commonly due to hematologic toxicity. Third was neurotoxicity, but when present it prompted drug discontinuation. These real-world data provide benchmarks to improve practice. [Table: see text].

Authors
Abernethy, AP; Zafar, Y; Marcello, J; Wheeler, J; Rowe, K; Morse, MA; Herndon, JE
MLA Citation
Abernethy, AP, Zafar, Y, Marcello, J, Wheeler, J, Rowe, K, Morse, MA, and Herndon, JE. "Treatment-related toxicity and supportive care in metastatic colorectal cancer (mCRC)." J Clin Oncol 26.15_suppl (May 20, 2008): 15087-.
PMID
27950327
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
15087

Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma.

4604 Background: Hepatocellular carcinomas (HCC) are known to express EGFR, and a ph II study of erlotinib suggested clinical activity of EGFR inhibition. Combinations with EGFR and chemotherapies have been synergistic in a number of settings. We therefore studied the efficacy of capecitabine (cape), oxaliplatin (ox) plus cetuximab (ctx) in patients with advanced HCC. METHODS: Patients had advanced/unresectable HCC by tissue dx or AFP>1,000. Prior chemoembolization was allowed, but no prior systemic therapy. EGFR testing was not required for entry. Patients were treated with cape 850 mg/m(2) bid for 14 days, ox 130 mg/m(2) iv q3wks and ctx 400 mg/m(2) on day one followed by 250 mg/m(2) weekly. A toxicity evaluation was performed after 10 patients were enrolled and doses continued at initial levels throughout the trial. Tumor evaluations were performed q 6 weeks. No particular Childs class was required, but bilirubin had to be < 3, and adequate hematologic and renal parameters were required. RESULTS: 24 of 25 planned pts have completed at least one cycle of therapy. 20 pts are evaluable for response. 2/20 (10%, 95% CI: 1%,-33%) had PR, 13(65%) SD and 5(25%) PD. The most frequent Grade 3 and 4 toxicities have included hyperbilirubinemia (n=8, 35%), fatigue (n = 7, 30%), hypomagnesemia (n = 6, 26%), diarrhea (n = 5, 22%), and hypocalcemia (n = 5, 22%). Three patients died within the first 30 days of treatment, one due to toxicity and 2 due to rapid disease progression. Median TTP is 4.3 mos (95% CI 2.3, 5.0). CONCLUSIONS: The combination of capecitabine, oxaliplating and cetuximab is tolerable for most patients, although diarrhea and electrolyte abnormalities are more pronounced in this population than in other patient populations and led to death in one patient. The combination is associated with a modest rate of radiographic response, but a high rate of stable disease and a promising TTP. Updated TTP and preliminary OS data will be presented at the meeting. [Table: see text].

Authors
O'Neil, BH; Bernard, SA; Goldberg, RM; Moore, DT; Garcia, R; Marroquin, C; Morse, MA; Woods, L; Sanoff, HK
MLA Citation
O'Neil, BH, Bernard, SA, Goldberg, RM, Moore, DT, Garcia, R, Marroquin, C, Morse, MA, Woods, L, and Sanoff, HK. "Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma." J Clin Oncol 26.15_suppl (May 20, 2008): 4604-.
PMID
27948498
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4604

A phase I study of Iobenguane I 131 to evaluate MTD, efficacy and safety in patients with malignant pheochromocytoma/paraganglioma (Pheo)

Authors
Morse, MA; Babich, JW; LaFrance, N; Kacena, KA; Gockerman, J; Moore, J; Coleman, RE
MLA Citation
Morse, MA, Babich, JW, LaFrance, N, Kacena, KA, Gockerman, J, Moore, J, and Coleman, RE. "A phase I study of Iobenguane I 131 to evaluate MTD, efficacy and safety in patients with malignant pheochromocytoma/paraganglioma (Pheo)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)

Authors
Hanks, BA; Suhocki, PV; DeLong, DM; Doan, PL; Liu, E; Tsai, AL; Burke, CT; Bernard, SA; O'Neil, BH; Morse, MA
MLA Citation
Hanks, BA, Suhocki, PV, DeLong, DM, Doan, PL, Liu, E, Tsai, AL, Burke, CT, Bernard, SA, O'Neil, BH, and Morse, MA. "The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma

Authors
O'Neil, BH; Bernard, SA; Goldberg, RM; Moore, DT; Garcia, R; Marroquin, C; Morse, MA; Woods, L; Sanoff, HK
MLA Citation
O'Neil, BH, Bernard, SA, Goldberg, RM, Moore, DT, Garcia, R, Marroquin, C, Morse, MA, Woods, L, and Sanoff, HK. "Phase II study of oxaliplatin, capecitabine, and cetuximab in advanced hepatocellular carcinoma." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines

Authors
Clay, TM; Hobeika, A; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Morse, MA
MLA Citation
Clay, TM, Hobeika, A, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Morse, MA. "Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines." May 20, 2008.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Induction of immune responses and clinical activity in a phase II trial of IDM-2101, a 10-epitope CTL vaccine, in metastatic NSCLC patients

Authors
Barve, M; Bender, J; Pappen, B; Ishioka, G; Morse, MA; Greco, FA; McCune, D; Steis, R; Khong, H; Nemunaitis, JJ; Network, MCMRT
MLA Citation
Barve, M, Bender, J, Pappen, B, Ishioka, G, Morse, MA, Greco, FA, McCune, D, Steis, R, Khong, H, Nemunaitis, JJ, and Network, MCMRT. "Induction of immune responses and clinical activity in a phase II trial of IDM-2101, a 10-epitope CTL vaccine, in metastatic NSCLC patients." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Initial results of a phase II study of oxaliplatin (OX), capecitabine (CAP), bevacizumab (BV), and cetuximab (CET) in the treatment of metastatic colorectal cancer (mCRC)

Authors
Bendell, JC; Uronis, HE; Morse, MA; Blobe, G; Aklilu, M; Nixon, A; Niedzweicki, D; Honeycutt, W; Howard, L; Hurwitz, H
MLA Citation
Bendell, JC, Uronis, HE, Morse, MA, Blobe, G, Aklilu, M, Nixon, A, Niedzweicki, D, Honeycutt, W, Howard, L, and Hurwitz, H. "Initial results of a phase II study of oxaliplatin (OX), capecitabine (CAP), bevacizumab (BV), and cetuximab (CET) in the treatment of metastatic colorectal cancer (mCRC)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Treatment-related toxicity and supportive care in metastatic colorectal cancer (mCRC)

Authors
Abernethy, AP; Zafar, Y; Marcello, J; Wheeler, J; Rowe, K; Morse, MA; II, HJE
MLA Citation
Abernethy, AP, Zafar, Y, Marcello, J, Wheeler, J, Rowe, K, Morse, MA, and II, HJE. "Treatment-related toxicity and supportive care in metastatic colorectal cancer (mCRC)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

E/Tablets to collect research-quality, patient-reported data

Authors
Uronis, HE; II, HJE; Coan, A; Bronson, K; Wheeler, J; Lyerly, HK; Morse, MA; Abernethy, AP
MLA Citation
Uronis, HE, II, HJE, Coan, A, Bronson, K, Wheeler, J, Lyerly, HK, Morse, MA, and Abernethy, AP. "E/Tablets to collect research-quality, patient-reported data." May 20, 2008.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Longitudinal patterns of chemotherapy (CT) use in metastatic colorectal cancer (mCRC)

Authors
II, HJE; Zafar, Y; Marcello, J; Wheeler, J; Rowe, K; Morse, MA; Abernethy, AP
MLA Citation
II, HJE, Zafar, Y, Marcello, J, Wheeler, J, Rowe, K, Morse, MA, and Abernethy, AP. "Longitudinal patterns of chemotherapy (CT) use in metastatic colorectal cancer (mCRC)." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines.

3010 Background: CD4+CD25+FoxP3+ regulatory T cells (Treg) limit antigen-specific immune responses and are a cause of suppressed anticancer immunity. Conversely, depletion of Treg leads to immune enhancement. The immunotoxin denileukin diftitox which selectively targets lymphocytes expressing CD25 may deplete FoxP3+ Treg.We evaluated the proliferative potential of PBMC to various antigens in vitro following exposure to denileukin diftitox. We then performed a pilot study in which patients with advanced CEA expressing malignancies, being immunized with autologous dendritic cells modified with a fowlpox vector encoding CEA (rF-CEA(6D)-TRICOM), received denileukin diftitox 18 mcg/kg, once, 4 days before the immunizations began, or 9 mcg/kg prior to each of the 4 immunizations. ELISPOT, cytokine flow cytometry, and ELISA were used to measure the T cell and antibody response.In vitro, escalating doses of denileukin diftitox depleted FoxP3+ Treg, decreased Treg function in vitro, and enhanced antigen-specific T cell responses. In the pilot study (n=15), denileukin diftitox was associated with a 74 ± 6% decrease in Treg in those receiving multiple doses, but not in those receiving a single dose. An earlier peak in the vaccine-induced CEA-specific T cell responses, and significant levels (>0.5%) of circulating CD8+ and CD4+ CEA-specific T cells were also seen in the multiple dose group. Conversely, a single dose of denileukin diftitox enhanced anti-CEA, but not antifowlpox vector, antibody responses. Multiple doses abolished the anti-CEA antibody response.These results indicate the potential for combining Treg depletion with anticancer vaccines to enhance tumor antigen specific immune responses. No significant financial relationships to disclose.

Authors
Clay, TM; Hobeika, A; Osada, T; Serra, D; Niedzwiecki, D; Lyerly, HK; Morse, MA
MLA Citation
Clay, TM, Hobeika, A, Osada, T, Serra, D, Niedzwiecki, D, Lyerly, HK, and Morse, MA. "Depletion of human regulatory T cells (Treg) and antigen-specific immune responses to cancer vaccines." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 3010-.
PMID
27947631
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
3010

Induction of immune responses and clinical activity in a phase II trial of IDM-2101, a 10-epitope CTL vaccine, in metastatic NSCLC patients.

8057 Background: IDM-2101 is a 10-peptide vaccine designed to induce multi-specific CTL responses against MHC class I epitopes of CEA, p53, HER-2/neu and MAGE 2/3. Seven epitopes are modified for enhanced MHC binding or heteroclitic T-cell activation and 2 epitopes are native wild-type (WT) sequences. Also included is the class II helper epitope PADRE. We report here immune responses and clinical activity from a Phase 2 trial of IDM-2101.68 HLA-A2+ good performance patients (pts) with Stage IIIB/IV or recurrent NSCLC were enrolled. Patients were required to have a tumor volume <125 cm2. Pts received 6 induction doses (0.5 mg/epitope) q3 wks followed by maintenance treatments at 2-3 month intervals. 63 pts were treated with one or more doses. 72 HLA-A2 negative pts who were otherwise eligible were retrospectively selected as relevant controls. Endpoints included survival, clinical responses and induction of immune responses. CTL responses in peripheral blood MNC were measured, at predefined time points, after a 10 day in vitro stimulation with peptide followed by an IFNγ ELISPOT assay.30 of 33 available pts (91%) that were monitored for CTL showed positive responses to 1 or more epitopes and 21 of 33 pts (64%) responded to at least 3 epitopes. All 9 vaccine epitopes were immunogenic in at least 1 patient. CTL responses were detected in 3 of 4 pts tested at 12 months. T helper-cell responses against PADRE measured with a direct IFNγ ELISPOT assay were observed in 18 of the 33 pts (55%) tested. Toxicities attributable to vaccine were mild and consisted mostly of injection site reactions. Clinical responses included 1 CR, 1 PR and SD of ≥3 months in 54 of 63 pts (86%). 14 pts completed 2 years of dosing and remain without evidence of progression. Interim analysis of one-year survival in IDM-2101 treated pts was 60%, compared to 49% in the HLA-A2 negative group and median survival for treated pts was 17.3 months compared to 12.0 months for pts in the HLA-A2 negative group. A trend toward longer survival was observed in pts who responded to more epitopes.IDM-2101 was well- tolerated, induced broadly-specific CTL responses and may provide a survival benefit in metastatic NSCLC patients. [Table: see text].

Authors
Barve, M; Bender, J; Pappen, B; Ishioka, G; Morse, MA; Greco, FA; McCune, D; Steis, R; Khong, H; Nemunaitis, JJ
MLA Citation
Barve, M, Bender, J, Pappen, B, Ishioka, G, Morse, MA, Greco, FA, McCune, D, Steis, R, Khong, H, and Nemunaitis, JJ. "Induction of immune responses and clinical activity in a phase II trial of IDM-2101, a 10-epitope CTL vaccine, in metastatic NSCLC patients." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 8057-.
PMID
27948910
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
8057

A phase I study of Iobenguane I 131 to evaluate MTD, efficacy and safety in patients with malignant pheochromocytoma/paraganglioma (Pheo).

4605 Background: I-131-iobenguane, a substrate for the norepinephrine transporter, has been shown to be effective in the treatment of neuroendocrine cancers such as Pheo. Non-radioactive iobenguane has been shown to inhibit uptake of radioiodinated iobenguane by tumors and has potential to cause cardiovascular AEs. Ultratrace Iobenguane I 131 (Ultratrace) is prepared so that the final drug product is devoid of cold iobenguane thereby enhancing tumor accumulation and limiting dose dependent AEs.Patients with metastatic/recurrent Pheo with >1 CT-measurable lesion scintigraphically visualized with Ultratrace were enrolled. Ultratrace dose escalation used a 3+3 modified Fibonacci design; initiated at 6.0 mCi/kg and escalated in 1.0 mCi/kg increments. Safety and efficacy data were obtained including tumor measurements by CT/MRI volume, RECIST criteria and tumor markers.15 patients enrolled in the dose escalation study. Data were available for analysis on 9 patients (mean age: 51 yrs; 4 males) from 3 dose groups (6, 7 and 8 mCi/kg up to a max. of 75 kg body weight). The median weight was 84.2 kg (range: 42, 126). Total administered dose ranges for each dose cohort were 333 to 428 mCi, 325 to 536 mCi, and 473 to 601 mCi, respectively. No protocol defined DLTs were observed at the 6 or 7 mCi/kg dose levels. One patient at the 8 mCi/kg dose experienced grade 4 thrombocytopenia, and no intervention was required. No CV effects were observed. At 3- and 6-month follow up, CT/MRI scans were available for 5 and 2 patients, respectively. All patients showed decreases in the longest diameter per RECIST (-15%, -18%, -6%, -10%, -10%; -15%, -24%), and 4 and 2 patients with available data showed decreases or stabilization in tumor volume (-28%, -25%, 0%, -17%; -29% and -46%). Also, all 5 patients showed a decline in serum chromogranin A levels (range: -22% to -75%) and other tumor markers, and ∼50% showed improvements in HTN and tumor pain.Reductions in tumor volume, tumor dimension per RECIST, and tumor markers were observed in all 5 evaluable patients at 3 months after a single Ultratrace dose. Improvements in HTN and pain occurred in ∼50%. Dose escalation is proceeding. [Table: see text].

Authors
Morse, MA; Babich, JW; LaFrance, N; Kacena, KA; Gockerman, J; Moore, J; Coleman, RE
MLA Citation
Morse, MA, Babich, JW, LaFrance, N, Kacena, KA, Gockerman, J, Moore, J, and Coleman, RE. "A phase I study of Iobenguane I 131 to evaluate MTD, efficacy and safety in patients with malignant pheochromocytoma/paraganglioma (Pheo)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 4605-.
PMID
27948499
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4605

The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC).

4595 Background: Radiologic procedures that involve embolizing branches of the hepatic artery lengthen survival for patients with unresectable HCC, but the benefit of administering intrahepatic arterial chemotherapy during the embolization procedure is uncertain.A retrospective review of all patients with HCC and undergoing an embolization in the last 10 years and with 2 years of follow-up data was undertaken at two institutions to compare the survival and TTP of patients receiving TACE compared with TAE. Prognostic factors analyzed included age, gender, race, largest tumor size, number of tumors, macrovascular invasion, AFP, Child's class, and CLIP score.122 pts with the following characteristics were included in the analysis: 71% Caucasian, 22% African American, 52% HCV+, 13% HBV+, 66% with cirrhosis, Child's A/B/C 70/25/5%, CLIP Score 0,1/2/>3 52/26/21%, 72% had either 1 or 2 tumors, 14% macrovascular invasion, 16% portal vein branch thrombosis, 20% extrahepatic disease. The procedure (TACE (51%, the majority receiving doxorubicin plus mitomycin C) and TAE (49%).was completed in one session in 87%. A subsequent embolization was performed in 37% for progression or new disease. The embolizing material was ethiodised oil in 39%, polyacrylamide/gelatin in 43%, and polyvinyl alcohol in 41%. The procedures were equally well tolerated. Although 37% of patients experienced an adverse event, readmission to the hospital was required in only 10%. One patient experienced fulminant hepatic failure. The median survival for TAE was 19.6 mo (95% CI 10.6-28.4) compared with 12.9mo (95% CI 7.0-19.5) for TACE (p=0.066). The TTP for TAE was 3.2mo (95% CI 2.1-6.0) compared with 4.1 mo (95% CI 2.1-5.6 for TACE (p=0.79). On multivariate analysis, the trend towards a difference in survival for TAE was eliminated and only CLIP score, AFP, and largest tumor remained as prognostic factors.This retropsective review suggests that adding chemotherapy to embolization does not improve survival compared with bland embolization in pts with HCC. Future efforts should focus on adjunctive therapies following the embolization to prevent progression or new primary tumors. No significant financial relationships to disclose.

Authors
Hanks, BA; Suhocki, PV; DeLong, DM; Doan, PL; Liu, E; Tsai, AL; Burke, CT; Bernard, SA; O'Neil, BH; Morse, MA
MLA Citation
Hanks, BA, Suhocki, PV, DeLong, DM, Doan, PL, Liu, E, Tsai, AL, Burke, CT, Bernard, SA, O'Neil, BH, and Morse, MA. "The efficacy and tolerability of transarterial chemo-embolization (TACE) compared with transarterial embolization (TAE) for patients with unresectable hepatocellular carcinoma (HCC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26.15_suppl (May 2008): 4595-.
PMID
27948705
Source
epmc
Published In
Journal of Clinical Oncology
Volume
26
Issue
15_suppl
Publish Date
2008
Start Page
4595

Precision and linearity targets for validation of an IFNgamma ELISPOT, cytokine flow cytometry, and tetramer assay using CMV peptides.

BACKGROUND: Single-cell assays of immune function are increasingly used to monitor T cell responses in immunotherapy clinical trials. Standardization and validation of such assays are therefore important to interpretation of the clinical trial data. Here we assess the levels of intra-assay, inter-assay, and inter-operator precision, as well as linearity, of CD8+ T cell IFNgamma-based ELISPOT and cytokine flow cytometry (CFC), as well as tetramer assays. RESULTS: Precision was measured in cryopreserved PBMC with a low, medium, or high response level to a CMV pp65 peptide or peptide mixture. Intra-assay precision was assessed using 6 replicates per assay; inter-assay precision was assessed by performing 8 assays on different days; and inter-operator precision was assessed using 3 different operators working on the same day. Percent CV values ranged from 4% to 133% depending upon the assay and response level. Linearity was measured by diluting PBMC from a high responder into PBMC from a non-responder, and yielded R2 values from 0.85 to 0.99 depending upon the assay and antigen. CONCLUSION: These data provide target values for precision and linearity of single-cell assays for those wishing to validate these assays in their own laboratories. They also allow for comparison of the precision and linearity of ELISPOT, CFC, and tetramer across a range of response levels. There was a trend toward tetramer assays showing the highest precision, followed closely by CFC, and then ELISPOT; while all three assays had similar linearity. These findings are contingent upon the use of optimized protocols for each assay.

Authors
Maecker, HT; Hassler, J; Payne, JK; Summers, A; Comatas, K; Ghanayem, M; Morse, MA; Clay, TM; Lyerly, HK; Bhatia, S; Ghanekar, SA; Maino, VC; Delarosa, C; Disis, ML
MLA Citation
Maecker, HT, Hassler, J, Payne, JK, Summers, A, Comatas, K, Ghanayem, M, Morse, MA, Clay, TM, Lyerly, HK, Bhatia, S, Ghanekar, SA, Maino, VC, Delarosa, C, and Disis, ML. "Precision and linearity targets for validation of an IFNgamma ELISPOT, cytokine flow cytometry, and tetramer assay using CMV peptides. (Published online)" BMC Immunol 9 (March 17, 2008): 9-.
PMID
18366814
Source
pubmed
Published In
BMC Immunology
Volume
9
Publish Date
2008
Start Page
9
DOI
10.1186/1471-2172-9-9

When is an adjuvant not an adjuvant? Overview.

Authors
Whelan, M; Morse, MA
MLA Citation
Whelan, M, and Morse, MA. "When is an adjuvant not an adjuvant? Overview." Curr Opin Mol Ther 10.1 (February 2008): 8-9.
PMID
18228176
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
10
Issue
1
Publish Date
2008
Start Page
8
End Page
9

Tumor antigens

© 2007 Springer. All Rights Reserved.The concept of specific immunotherapy depends on the notion that tumors may be specifically targeted by immune effectors such as T cells and antibodies that distinguish distinct differences between normal tissues and tumors. This is in contrast to the concept of non-specific immunotherapy which is mediated by effectors such as NK cells that kill tumor in a non-antigen dependent fashion. Tumor antigens are protein, peptide, or carbohydrate molecules that the immune system uses to distinguish tumor cells from normal cells. While target antigens in the form of surface proteins or carbohydrates that may be recognized by antibodies had been well accepted for quite some time, it was not until observations on the MHC-restricted killing of tumor cells by cytolytic T cells, that attempts were made to clone the genes that encoded the antigens recognized by the T cells. In 1991, the first human tumor antigen recognized by T cells, called MAGE-1, was first discovered [1]. The ensuing years saw an explosion in the number of tumor antigens described and an even greater growth in the number of immunogenic peptide epitopes present within these antigenic molecules. These have now been catalogued in recent, excellent reviews [2] or published on websites (http://www.cancerimmunity.org/peptidedatabase/differentiation.htm). To create some order to the long list of varied antigens, it is helpful to group them according to their expression patterns (for example, cancer-testis antigens found predominantly in tumors or germ cells or differentiation antigens, found predominantly during fetal development in normal tissues) and we will discuss them in this order. Nonetheless, the purpose of this chapter is not to recapitulate the information collected in these publications, but to briefly describe the categories of tumor antigens, explain their relevance to cancer immunotherapy strategies, and to discuss how tumor antigens are discovered. Also, while some tumor antigens may be recognized by T cells or antibodies, we will focus on the antigens recognized by T cells, the primary immune effector for destroying tumor cells.

Authors
Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, and Lyerly, HK. "Tumor antigens." General Principles of Tumor Immunotherapy: Basic and Clinical Applications of Tumor Immunology. January 1, 2008. 17-31.
Source
scopus
Publish Date
2008
Start Page
17
End Page
31
DOI
10.1007/978-1-4020-6087-8_2

Foreword

Authors
Morse, M
MLA Citation
Morse, M. "Foreword." January 1, 2008.
Website
http://hdl.handle.net/10161/7951
Source
scopus
Volume
8
Publish Date
2008

Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression.

Inflammatory breast cancer (IBC) patients show poor survival and a significant incidence of epidermal growth factor receptor-2 (ErbB2) overexpression. A distinct mechanism involving increased expression of X-linked inhibitor of apoptosis protein (XIAP) and survivin, key members of the inhibitor of apoptosis protein (IAP) family, was observed post-trastuzumab (an ErbB2 monoclonal antibody) treatment in an ErbB2-overexpressing, estrogen receptor negative, IBC cellular model, SUM190PT, isolated from a primary IBC tumor. In contrast, a decrease in the IAP expression was observed in the non-IBC, ErbB2-overexpressing SKBR3 cells in which trastuzumab treatment also decreased p-AKT and cell viability. Further, in SUM190PT cells, therapeutic sensitivity to GW583340 (a dual epidermal growth factor receptor/ErbB2 kinase inhibitor) corresponded with XIAP down-regulation and abrogation of XIAP inhibition on active caspase-9 release. Specific small interfering RNA-mediated XIAP inhibition in combination with trastuzumab caused decrease in inactive procaspase-9 and inhibition of p-AKT corresponding with 45% to 50% decrease in cell viability in the SUM190PT cells, which have high steady-state p-AKT levels. Further, embelin, a small-molecule inhibitor that abrogates binding of XIAP to procaspase-9, caused significant decrease in SUM190PT viability. However, embelin in combination with trastuzumab failed to affect SUM190PT viability because it has no direct effect on XIAP, which is induced by trastuzumab treatment. These data have identified a novel functional link between ErbB2 signaling and antiapoptotic pathway mediated by XIAP. Blockade of the IAP antiapoptotic pathway alone or in combination would be an attractive strategy in IBC therapy.

Authors
Aird, KM; Ding, X; Baras, A; Wei, J; Morse, MA; Clay, T; Lyerly, HK; Devi, GR
MLA Citation
Aird, KM, Ding, X, Baras, A, Wei, J, Morse, MA, Clay, T, Lyerly, HK, and Devi, GR. "Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression." Mol Cancer Ther 7.1 (January 2008): 38-47.
PMID
18202008
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
7
Issue
1
Publish Date
2008
Start Page
38
End Page
47
DOI
10.1158/1535-7163.MCT-07-0370

Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases.

BACKGROUND: Although commonly used in combination with irinotecan or oxaliplatin (iri/oxal) for treatment of colorectal liver metastases before extirpation, the effects of preoperative bevacizumab on surgical outcomes are not established. The objective of this retrospective study was to determine if addition of bevacizumab to iri/oxal preoperative chemotherapy increases morbidity after hepatic resection. STUDY DESIGN: We compared demographics, clinicopathologic data, treatments, and postoperative outcomes between patients given preoperative iri/oxal with and without bevacizumab and patients who underwent hepatic resection within and after 8 weeks from the last dose of bevacizumab. RESULTS: From 1996 to 2006, 96 patients were treated with preoperative iri/oxal; 39 (40.6%) received concurrent bevacizumab. Preoperative bevacizumab treatment was associated with less blood loss (median 425 mL versus 600 mL, p=0.01) and lower RBC transfusion rates (43.9% versus 23.1%, p=0.06) after partial hepatectomy on univariable analysis. Only age>or=70 years (hazard ratio=8.52, 95% CI [2.00 to 36.45]) and concurrent extrahepatic procedures (hazard ratio=4.12, 95% CI [1.49 to 11.39]) independently predicted RBC transfusion and overall complications, respectively. There were no differences in overall (43.6% versus 38.6%), severe (28.2% versus 24.6%), hepatic (17.9% versus 26.3%), wound (10.3% versus 7%), or thromboembolic or bleeding (2.6% versus 5.3%) complications (all p > 0.05). For patients treated with iri/oxal and bevacizumab, overall complications were more common when resection was performed within 8 weeks after the last bevacizumab dose (62.5% versus 30.4%), but this difference was not statistically significant (p=0.06). CONCLUSIONS: If discontinued at least 8 weeks before hepatic resection, addition of bevacizumab to preoperative iri/oxal does not increase morbidity after hepatic resection.

Authors
Reddy, SK; Morse, MA; Hurwitz, HI; Bendell, JC; Gan, TJ; Hill, SE; Clary, BM
MLA Citation
Reddy, SK, Morse, MA, Hurwitz, HI, Bendell, JC, Gan, TJ, Hill, SE, and Clary, BM. "Addition of bevacizumab to irinotecan- and oxaliplatin-based preoperative chemotherapy regimens does not increase morbidity after resection of colorectal liver metastases." J Am Coll Surg 206.1 (January 2008): 96-106.
PMID
18155574
Source
pubmed
Published In
Journal of the American College of Surgeons
Volume
206
Issue
1
Publish Date
2008
Start Page
96
End Page
106
DOI
10.1016/j.jamcollsurg.2007.06.290

Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease.

BACKGROUND: Cytomegalovirus (CMV) infection and its treatment causes significant morbidity following allogeneic stem cell transplantation (SCT) for malignancies. We studied the phenotype, function and growth kinetics of CMV pp65 antigen (Ag)-specific T cells expanded in a short-term culture for adoptive therapy. METHODS: Peripheral blood mononuclear cells (PBMC) from CMV-seropositive donors were cultured in various conditions with CMV pp65((495-503)) peptide to determine the most effective method for generating CMV-specific T cells. CMV-expanded cultures were tested for frequency, phenotype and functionality using peptide-MHC tetramer analysis, cytokine flow cytometry and cytolytic assays. A patient undergoing allogeneic SCT was administered CMV pp65-specific T cells generated from the donor based on these data, and recipient PBMC were analyzed following T-cell infusion. RESULTS: CMV pp65-specific T cells were consistently generated from CMV-seropositive donors at high frequencies (20-40% of CD8+ T cells), secreted interferon-gamma (IFN-gamma) in response to CMV peptide and had lytic activity against CMV peptide-expressing targets. Cultured CMV-specific T cells were infused into a SCT recipient without toxicity. DISCUSSION: Stimulating donor PBMC to generate functional, Ag-specific T cells for infusion into SCT recipients was accomplished consistently using readily available technology. We observed no toxicity in one patient receiving T cells and were able to monitor infused cells. These findings support further study of this approach as a prophylaxis against the risk of infection in patients receiving allogeneic transplantation from CMV-seropositive donors.

Authors
Hobeika, A; Osada, T; Serra, D; Peplinski, S; Hanson, K; Tanaka, Y; Niedzwiecki, D; Chao, N; Rizzieri, D; Lyerly, H; Clay, T; Morse, M
MLA Citation
Hobeika, A, Osada, T, Serra, D, Peplinski, S, Hanson, K, Tanaka, Y, Niedzwiecki, D, Chao, N, Rizzieri, D, Lyerly, H, Clay, T, and Morse, M. "Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease." Cytotherapy 10.3 (2008): 289-302.
PMID
18418774
Source
pubmed
Published In
Cytotherapy (Informa)
Volume
10
Issue
3
Publish Date
2008
Start Page
289
End Page
302
DOI
10.1080/14653240801927040

Radioiodinated metaiodobenzylguanidine in the diagnosis and therapy of carcinoid tumors

Carcinoid tumors account for less than 1% of all malignancies and the majority arises in the gastrointestinal system. These tumors are slow-growing compared with adenocarcinomas and they differ from the other neuroendocrine malignancies by their protean clinical presentation. Carcinoid tumors were previously considered indolent, but they can manifest malignant characteristics with metastatic spread which often results in a poor prognosis. Although there have been advances in diagnostic and treatment modalities, carcinoid tumors are still frequently diagnosed late, often when the tumor has metastasized and patients have developed carcinoid syndrome. Diagnosis, prognosis and treatment options are based on biochemical markers and imaging investigations. High concentration of urinary 5-HIAA, elevated plasma serotonin and chromogranin A levels help to establish the initial diagnosis of carcinoid tumors. In addition to the computed tomography and magnetic resonance imaging, molecular imaging modalities such as OctreoScan, metaiodobenzylguanidine (MIBG) imaging and more recently PET imaging are used in detecting the primary malignancy and metastatic involvement. Surgery is the mainstay of treatment of non-metastatic carcinoid tumors. Cytotoxic chemotherapy has limited role because of the chemoresistant nature of these tumors. Because carcinoid tumors express somatostatin receptors, somatostatin analogues, which inhibit release of serotonin and other neuroendocrine peptides, are often used, but their use is limited to symptom control. Treatment using high doses of radionuclides, such as radiolabeled somatostatin analogues and MIBG, is a more recent option, which offers a definite advantage in management. In this article, we review the current state of the art in the diagnosis and treatment of carcinoid tumors as well as the role of MIBG in their diagnosis and management.

Authors
Khan, MU; Morse, M; Coleman, RE
MLA Citation
Khan, MU, Morse, M, and Coleman, RE. "Radioiodinated metaiodobenzylguanidine in the diagnosis and therapy of carcinoid tumors." Quarterly Journal of Nuclear Medicine and Molecular Imaging 52.4 (2008): 441-454.
PMID
19088697
Source
scival
Published In
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
Volume
52
Issue
4
Publish Date
2008
Start Page
441
End Page
454

Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer

Purpose: Generation of broad cytotoxic T-lymphocyte responses against multiple epitopes and tumor-associated antigens (TAAs) may provide effective immunotherapy in patients with cancer. We evaluated a single-vial peptide vaccine consisting of nine HLA-A2 supertype-binding epitopes (two native and seven analog epitopes modified for optimal HLA binding or T-cell receptor stimulation) covering five TAAs and the universal helper pan-DR epitope, formulated as a stable emulsion with incomplete Freund's adjuvant (Montanide ISA 51; Seppic SA, Paris, France). The clinical efficacy, safety, and multiepitope immunogenicity of IDM-2101 was evaluated in patients with stage IIIB or IV non-small-cell lung cancer (NSCLC). Patients and Methods: A total of 63 patients were enrolled who were positive for HLA-A2. End points included survival, safety, and immune response. IDM-2101 (previously EP-2101) was administered every 3 weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, for a total of 13 doses. Epitope-specific cytotoxic and helper T-lymphocyte immunogenic responses were measured by the interferon gamma enzyme-linked immunosorbent spot assay. Results: No significant adverse events were noted. Low-grade erythema and pain at the injection site were the most common adverse effects. One-year survival in the treated patients was 60%, and median survival was 17.3 months. One complete and one partial response were identified. Survival was longer in patients demonstrating an immune response to epitope peptides (P < .001). Conclusion: IDM-2101 was well tolerated, and evidence of efficacy was suggested. © 2008 by American Society of Clinical Oncology.

Authors
Barve, M; Bender, J; Senzer, N; Cunningham, C; Greco, FA; McCune, D; Steis, R; Khong, H; Richards, D; Stephenson, J; Ganesa, P; Nemunaitis, J; Ishioka, G; Pappen, B; Nemunaitis, M; Morse, M; Mills, B; Maples, PB; Sherman, J; Nemunaitis, JJ
MLA Citation
Barve, M, Bender, J, Senzer, N, Cunningham, C, Greco, FA, McCune, D, Steis, R, Khong, H, Richards, D, Stephenson, J, Ganesa, P, Nemunaitis, J, Ishioka, G, Pappen, B, Nemunaitis, M, Morse, M, Mills, B, Maples, PB, Sherman, J, and Nemunaitis, JJ. "Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer." Journal of Clinical Oncology 26.27 (2008): 4418-4425.
PMID
18802154
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
27
Publish Date
2008
Start Page
4418
End Page
4425
DOI
10.1200/JCO.2008.16.6462

An odd but synergistic couple: Immunotherapy combined with radiotherapy

In summary, there is considerable promise for combinations of immunotherapy with radiotherapy, but clinical experience is still limited. Preclinical models with greater relevance to human tumors should be used to continue identifying the best combinations and timing of radiation therapy and immunotherapy, but of course, only clinical trials will establish the true value of these combinations. Because we are entering an era with numerous therapies for cancer, all of which might act synergistically, the importance of patient selection is paramount. Predictive factors that indicate which patients are most likely to benefit from immunotherapy or radiation therapy are critically needed.

Authors
Morse, MA; Willett, CG
MLA Citation
Morse, MA, and Willett, CG. "An odd but synergistic couple: Immunotherapy combined with radiotherapy." ONCOLOGY 22.9 (2008): 1075-1080.
Source
scival
Published In
Oncology
Volume
22
Issue
9
Publish Date
2008
Start Page
1075
End Page
1080

Comment regarding benefit in phase 1 oncology trials

Authors
Morse, M
MLA Citation
Morse, M. "Comment regarding benefit in phase 1 oncology trials." Clinical Trials 5.6 (2008): 626--.
PMID
19029212
Source
scival
Published In
Clinical Trials
Volume
5
Issue
6
Publish Date
2008
Start Page
626-
DOI
10.1177/1740774508098682

Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3- galactose

Background: Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, is approved for use in colorectal cancer and squamouscell carcinoma of the head and neck. A high prevalence of hypersensitivity reactions to cetuximab has been reported in some areas of the United States. Methods: We analyzed serum samples from four groups of subjects for IgE antibodies against cetuximab: pretreatment samples from 76 case subjects who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas, and North Carolina; samples from 72 control subjects in Tennessee; samples from 49 control subjects with cancer in northern California; and samples from 341 female control subjects in Boston. Results: Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction to the drug. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these subjects; only 1 of 51 subjects who did not have a hypersensitivity reaction had such antibodies (P<0.001). IgE antibodies against cetuximab were found in 15 of 72 samples (20.8%) from control subjects in Tennessee, in 3 of 49 samples (6.1%) from northern California, and in 2 of 341 samples (0.6%) from Boston. The IgE antibodies were shown to be specific for an oligosaccharide, galactose-α-1,3-galactose, which is present on the Fab portion of the cetuximab heavy chain. Conclusions: In most subjects who had a hypersensitivity reaction to cetuximab, IgE antibodies against cetuximab were present in serum before therapy. The antibodies were specific for galactose-α-1,3- galactose. Copyright © 2008 Massachusetts Medical Society.

Authors
Chung, CH; Mirakhur, B; Chan, E; Le, Q-T; Berlin, J; Morse, M; Murphy, BA; Satinover, SM; Hosen, J; Mauro, D; Slebos, RJ; Zhou, Q; Gold, D; Hatley, T; Hicklin, DJ; Platts-Mills, TAE
MLA Citation
Chung, CH, Mirakhur, B, Chan, E, Le, Q-T, Berlin, J, Morse, M, Murphy, BA, Satinover, SM, Hosen, J, Mauro, D, Slebos, RJ, Zhou, Q, Gold, D, Hatley, T, Hicklin, DJ, and Platts-Mills, TAE. "Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3- galactose." New England Journal of Medicine 358.11 (2008): 1109-1117.
PMID
18337601
Source
scival
Published In
The New England journal of medicine
Volume
358
Issue
11
Publish Date
2008
Start Page
1109
End Page
1117
DOI
10.1056/NEJMoa074943

When is an adjuvant not an adjuvant?

Authors
Whelan, M; Morse, MA
MLA Citation
Whelan, M, and Morse, MA. "When is an adjuvant not an adjuvant?." Current Opinion in Molecular Therapeutics 10.1 (2008): 8-9.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
10
Issue
1
Publish Date
2008
Start Page
8
End Page
9

Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer

Purpose: As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC. Patients and Methods: In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique. Results: Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P = .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P = .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors. Conclusion: The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies. © 2008 by American Society of Clinical Oncology.

Authors
Cohen, SJ; Punt, CJA; Iannotti, N; Saidman, BH; Sabbath, KD; Gabrail, NY; Picus, J; Morse, M; Mitchell, E; Miller, MC; Doyle, GV; Tissing, H; Terstappen, LWMM; Meropol, NJ
MLA Citation
Cohen, SJ, Punt, CJA, Iannotti, N, Saidman, BH, Sabbath, KD, Gabrail, NY, Picus, J, Morse, M, Mitchell, E, Miller, MC, Doyle, GV, Tissing, H, Terstappen, LWMM, and Meropol, NJ. "Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer." Journal of Clinical Oncology 26.19 (2008): 3213-3221.
PMID
18591556
Source
scival
Published In
Journal of Clinical Oncology
Volume
26
Issue
19
Publish Date
2008
Start Page
3213
End Page
3221
DOI
10.1200/JCO.2007.15.8923

Foreword

Authors
Morse, M
MLA Citation
Morse, M. "Foreword." Expert Opinion on Biological Therapy 8.1 (2008).
Source
scival
Published In
Expert Opinion on Biological Therapy
Volume
8
Issue
1
Publish Date
2008

Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy.

PURPOSE: To report patterns of disease recurrence after resection of adenocarcinoma of the duodenum and compare outcomes between patients undergoing surgery only vs. surgery with concurrent chemotherapy and radiation therapy (CT-RT). METHODS AND MATERIALS: This was a retrospective analysis of all patients undergoing potentially curative therapy for adenocarcinoma of the duodenum at Duke University Medical Center and affiliated hospitals between 1975 and 2005. Overall survival (OS), disease-free survival (DFS), and local control (LC) were estimated using the Kaplan-Meier method. Univariate regression analysis evaluated the effect of CT-RT on clinical endpoints. RESULTS: Thirty-two patients were identified (23 M, 9 F). Median age was 60 years (range, 32-77 years). Surgery alone was performed in 16 patients. An additional 16 patients received either preoperative (n = 11) or postoperative (n = 5) CT-RT. Median RT dose was 50.4 Gy (range, 12.6-54 Gy). All patients treated with RT also received concurrent 5-fluorouracil-based CT. Two patients treated preoperatively had a pathologic complete response (18%), and none had involved lymph nodes at resection. Five-year OS, DFS, and LC for the entire group were 48%, 47%, and 55%, respectively. Five-year survival did not differ between patients receiving CT-RT vs. surgery alone (57% vs. 44%, p = 0.42). However, in patients undergoing R0 resection, CT-RT appeared to improve OS (5-year 83% vs. 53%, p = 0.07). CONCLUSIONS: Local failure after surgery alone is high. Given the patterns of relapse with surgery alone and favorable outcomes in patients undergoing complete resection with CT-RT, the use of CT-RT in selected patients should be considered.

Authors
Kelsey, CR; Nelson, JW; Willett, CG; Chino, JP; Clough, RW; Bendell, JC; Tyler, DS; Hurwitz, HI; Morse, MA; Clary, BM; Pappas, TN; Czito, BG
MLA Citation
Kelsey, CR, Nelson, JW, Willett, CG, Chino, JP, Clough, RW, Bendell, JC, Tyler, DS, Hurwitz, HI, Morse, MA, Clary, BM, Pappas, TN, and Czito, BG. "Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy." Int J Radiat Oncol Biol Phys 69.5 (December 1, 2007): 1436-1441.
PMID
17689032
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
5
Publish Date
2007
Start Page
1436
End Page
1441
DOI
10.1016/j.ijrobp.2007.05.006

Simultaneous resections of colorectal cancer and synchronous liver metastases: a multi-institutional analysis.

BACKGROUND: The safety of simultaneous resections of colorectal cancer and synchronous liver metastases (SCRLM) is not established. This multi-institutional retrospective study compared postoperative outcomes after simultaneous and staged colorectal and hepatic resections. METHODS: Clinicopathologic data, treatments, and postoperative outcomes from patients who underwent simultaneous or staged colorectal and hepatic resections at three hepatobiliary centers from 1985-2006 were reviewed. RESULTS: 610 patients underwent simultaneous (n = 135) or staged (n = 475) resections of colorectal cancer and SCRLM. Seventy staged patients underwent colorectal and hepatic resections at the same institution. Simultaneous patients had fewer (median 1 versus 2) and smaller (median 2.5 versus 3.5 cm) metastases and less often underwent major (> or = three segments) hepatectomy (26.7% versus 61.3%, p < 0.05). Combined hospital stay was lower after simultaneous resections (median 8.5 versus 14 days, p < 0.0001). Mortality (1.0% versus 0.5%) and severe morbidity (14.1% versus 12.5%) were similar after simultaneous colorectal resection and minor hepatectomy compared with isolated minor hepatectomy (both p > 0.05). For major hepatectomy, simultaneous colorectal resection increased mortality (8.3% versus 1.4%, p < 0.05) and severe morbidity (36.1% versus 15.1%, p < 0.05). Combined severe morbidity after staged resections was lower compared to simultaneous resections (36.1% versus 17.6%, p = 0.05) for major hepatectomy but similar for minor hepatectomy (14.1% versus 10.5%, p > 0.05). Major hepatectomy independently predicted severe morbidity after simultaneous resections [hazard ratio (HR) = 3.4, p = 0.008]. CONCLUSIONS: Simultaneous colorectal and minor hepatic resections are safe and should be performed for most patients with SCRLM. Due to increased risk of severe morbidity, caution should be exercised before performing simultaneous colorectal and major hepatic resections.

Authors
Reddy, SK; Pawlik, TM; Zorzi, D; Gleisner, AL; Ribero, D; Assumpcao, L; Barbas, AS; Abdalla, EK; Choti, MA; Vauthey, J-N; Ludwig, KA; Mantyh, CR; Morse, MA; Clary, BM
MLA Citation
Reddy, SK, Pawlik, TM, Zorzi, D, Gleisner, AL, Ribero, D, Assumpcao, L, Barbas, AS, Abdalla, EK, Choti, MA, Vauthey, J-N, Ludwig, KA, Mantyh, CR, Morse, MA, and Clary, BM. "Simultaneous resections of colorectal cancer and synchronous liver metastases: a multi-institutional analysis." Ann Surg Oncol 14.12 (December 2007): 3481-3491.
PMID
17805933
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
14
Issue
12
Publish Date
2007
Start Page
3481
End Page
3491
DOI
10.1245/s10434-007-9522-5

Assessing the quality of colorectal cancer care: do we have appropriate quality measures? (A systematic review of literature).

RATIONALE, AIMS AND OBJECTIVES: The burden of illness from colorectal cancer (CRC) can be reduced by improving the quality of care. Identifying appropriate quality measures is the first step in this direction. We identified process measures currently available to assess the quality of diagnosis and management of CRC. We also evaluated the extent to which these measures are ready to be implemented in clinical practice, and identified areas for future research. METHODS: We searched MEDLINE, Cochrane Database of Systematic Reviews, and relevant grey literature. We identified 3771 abstracts and reviewed 74 articles that included quality measures for diagnosis or management of CRC. Measures from traditional quality improvement literature, and from epidemiological and other studies that included quality measures as part of their research agenda, were considered. In addition, we devised a summary rating scale (IST) to appraise the extent of a measure's importance and usability, scientific acceptability and extent of testing. RESULTS: The coverage of general process measures in CRC is extensive. Most measures are important, but need to be developed and field-tested. The best available measures relate to pathology and chemotherapy. No measures are available for assessing quality of management of stage IV rectal cancer and hepatic metastasis; chemotherapy for stage II colon cancer; and procedure notes. CONCLUSIONS: There is an urgent need to refine existing measures and to develop scientifically accurate quality measures for a comprehensive assessment of the quality of CRC care. The role of the federal government and professional societies is critical in pursuing this goal.

Authors
Patwardhan, M; Fisher, DA; Mantyh, CR; McCrory, DC; Morse, MA; Prosnitz, RG; Cline, K; Samsa, GP
MLA Citation
Patwardhan, M, Fisher, DA, Mantyh, CR, McCrory, DC, Morse, MA, Prosnitz, RG, Cline, K, and Samsa, GP. "Assessing the quality of colorectal cancer care: do we have appropriate quality measures? (A systematic review of literature)." J Eval Clin Pract 13.6 (December 2007): 831-845. (Review)
PMID
18070253
Source
pubmed
Published In
Journal of Evaluation in Clinical Practice
Volume
13
Issue
6
Publish Date
2007
Start Page
831
End Page
845
DOI
10.1111/j.1365-2753.2006.00762.x

Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer.

PURPOSE: To compare a neoadjuvant regimen of cisplatin/5-fluorouracil (5-FU) and concurrent radiation therapy (RT) with paclitaxel-based regimens and RT in the management of operable esophageal (EC)/gastroesophageal junction (GEJ) cancer. METHODS AND MATERIALS: All patients receiving neoadjuvant chemotherapy (CT) and RT for EC/GEJ cancer at Duke University between January 1995 and December 2004 were included. Clinical end points were compared for patients receiving paclitaxel-based regimens (TAX) vs. alternative regimens (non-TAX). Local control (LC), disease-free survival (DFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Chi-square analysis was performed to test the effect of TAX on pathologic complete response (pCR) rates and toxicity. RESULTS: A total of 109 patients received CT-RT followed by esophagectomy (95 M; 14 F). Median RT dose was 45 Gy (range, 36-66 Gy). The TAX and non-TAX groups comprised 47% and 53% of patients, respectively. Most (83%) TAX patients received three drug regimens including platinum and a fluoropyrimidine. In the non-TAX group, 89% of the patients received cisplatin and 5-FU. The remainder received 5-FU or capecitabine alone. Grade 3-4 toxicity occurred in 41% of patients receiving TAX vs. 24% of those receiving non-TAX (p = 0.19). Overall pCR rate was 39% (39% with TAX vs. 40% with non-TAX, p = 0.9). Overall LC, DFS, and OS at 3 years were 80%, 34%, and 37%, respectively. At 3 years, there were no differences in LC (75% vs. 85%, p = 0.33) or OS (37% vs. 37%, p = 0.32) between TAX and non-TAX groups. CONCLUSIONS: In this large experience, paclitaxel-containing regimens did not improve pCR rates or clinical end points compared to non-paclitaxel-containing regimens.

Authors
Kelsey, CR; Chino, JP; Willett, CG; Clough, RW; Hurwitz, HI; Morse, MA; Bendell, JC; D'Amico, TA; Czito, BG
MLA Citation
Kelsey, CR, Chino, JP, Willett, CG, Clough, RW, Hurwitz, HI, Morse, MA, Bendell, JC, D'Amico, TA, and Czito, BG. "Paclitaxel-based chemoradiotherapy in the treatment of patients with operable esophageal cancer." Int J Radiat Oncol Biol Phys 69.3 (November 1, 2007): 770-776.
PMID
17889266
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
3
Publish Date
2007
Start Page
770
End Page
776
DOI
10.1016/j.ijrobp.2007.03.035

Medical and Innovative Therapies for Biliary Malignancies

Authors
Morse, MA; Pestalozzi, B
MLA Citation
Morse, MA, and Pestalozzi, B. "Medical and Innovative Therapies for Biliary Malignancies." (October 25, 2007): 205-214. (Chapter)
Source
scopus
Publish Date
2007
Start Page
205
End Page
214
DOI
10.1002/9780470986981.ch11

Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment: Second Edition

An interdisciplinary reference book for the diagnosis and treatment of gallbladder and bile duct diseases. With recent developments in the management of hepatobiliary diseases including liver transplantation, this new edition aids all members of the team by addressing both the biliary indications for and biliary complications of these procedures. It's divided into three sections on anatomy, pathophysiology, and epidemiology; diagnostic and therapeutic approaches including the latest therapeutic modalities; and specific conditions. Includes more than 250 illustrations for rapid reference. Each chapter now has a Q and A section and begins with a list of objectives outlining the chapter's goals. In addition, a number of new imaging modalities are presented in this new edition. It takes an integrated medical, surgical and radiological approach, making this invaluable to all members of the team who deal with complications of liver transplantation and the management of patients. © 2006 by Blackwell Publishing Ltd.

Authors
Clavien, PA; Baillie, J; Morse, MA; Selzner, M
MLA Citation
Clavien, PA, Baillie, J, Morse, MA, and Selzner, M. "Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment: Second Edition." Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment: Second Edition (October 25, 2007): 1-428.
Source
scopus
Published In
Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment: Second Edition
Publish Date
2007
Start Page
1
End Page
428
DOI
10.1002/9780470986981

Current immunotherapeutic strategies in colon cancer.

Because chemotherapy is standard in the treatment of colorectal cancer, it is important to demonstrate whether immunizations may be given to patients receiving systemic chemotherapy. Although some studies have demonstrated immune responses in patients with metastatic colorectal carcinoma who failed standard chemotherapy, the setting of minimal residual disease may be the preferred setting for cancer vaccines. It may be important to choose antigens that have functions important to the cancer cell. The best adjuvant is not well established and may depend on the type of immune response desired. The immune system is "programmed" to down-regulate immune responses once they have become activated to avoid the development of autoimmune disease.

Authors
Morse, M; Langer, L; Starodub, A; Hobeika, A; Clay, T; Lyerly, HK
MLA Citation
Morse, M, Langer, L, Starodub, A, Hobeika, A, Clay, T, and Lyerly, HK. "Current immunotherapeutic strategies in colon cancer." Surg Oncol Clin N Am 16.4 (October 2007): 873-x. (Review)
PMID
18022550
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
16
Issue
4
Publish Date
2007
Start Page
873
End Page
x
DOI
10.1016/j.soc.2007.07.005

Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2.

BACKGROUND: The HER2-inhibiting antibody trastuzumab, in combination with chemotherapy, significantly improves survival of women with resected, HER2-overexpressing breast cancers, but is associated with toxicities including a risk of cardiomyopathy. Additionally, the beneficial effect of trastuzumab is expected to decrease once the drug is discontinued. We proposed to address these concerns by using cancer vaccines to stimulate HER2 intracellular domain (ICD)-specific T cell and antibody responses. METHODS: Subjects with stage II (> or = 6 +LN), III, or stage IV breast cancer with > 50% HER2 overexpressing tumor cells who were disease-free after surgery and adjuvant therapy were eligible. Vaccines consisted of immature, cultured DC (n = 3), mature cultured DC (n = 3), or mature Flt3-ligand mobilized peripheral blood DC (n = 1) loaded with ICD, or tetanus toxoid, keyhole limpet hemocyanin or CMV peptide as controls, and were administered intradermally/subcutaneously four times at 3 week intervals. ICD-specific T cell and antibody responses were measured. Cardiac function was determined by MUGA or ECHO; long term disease status was obtained from patient contact. RESULTS: All seven patients successfully underwent DC generation and five received all 4 immunizations. There were no toxicities greater than grade 1 or ejection fraction decrements below normal. Delayed-type hypersensitivity (DTH) reactions at the injection site occurred in 6/7 patients and HER2 specificity was detected by cytokine flow cytometry or ELISPOT in 5 patients. At more than 5 years of follow-up, 6/7 had detectable anti-ICD antibodies. One patient experienced a pulmonary recurrence at 4 years from their study immunizations. This recurrence was resected and they are without evidence of disease. All patients are alive and disease-free at 4.6-6.7 years of follow-up. CONCLUSION: Although this was a small pilot study, the well-tolerated nature of the vaccines, the lack of cardiac toxicity, significant immunogenicity, and a 100% 4.5-year survival rate suggest that vaccination with HER2 ICD protein-containing DC is appropriate for further study in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT00005956.

Authors
Morse, MA; Hobeika, A; Osada, T; Niedzwiecki, D; Marcom, PK; Blackwell, KL; Anders, C; Devi, GR; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Hobeika, A, Osada, T, Niedzwiecki, D, Marcom, PK, Blackwell, KL, Anders, C, Devi, GR, Lyerly, HK, and Clay, TM. "Long term disease-free survival and T cell and antibody responses in women with high-risk Her2+ breast cancer following vaccination against Her2. (Published online)" J Transl Med 5 (September 6, 2007): 42-.
PMID
17822557
Source
pubmed
Published In
Journal of Translational Medicine
Volume
5
Publish Date
2007
Start Page
42
DOI
10.1186/1479-5876-5-42

CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy.

Stimulation of toll-like receptor (TLR)9 activates human plasmacytoid dendritic cells and B cells, and induces potent innate immune responses in preclinical tumor models and in patients. CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. PF-3512676 (ProMune) was developed as a TLR9 agonist for the treatment of cancer as monotherapy and as an adjuvant in combination with chemo- and immunotherapy. Phase I and II trials have tested this drug in several hematopoietic and solid tumors. Pfizer has initiated Phase III trials to test PF-3512676 in combination with standard chemotherapy for non-small-cell lung cancer.

Authors
Murad, YM; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Murad, YM, Clay, TM, Lyerly, HK, and Morse, MA. "CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy." Expert Opin Biol Ther 7.8 (August 2007): 1257-1266. (Review)
PMID
17696823
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
7
Issue
8
Publish Date
2007
Start Page
1257
End Page
1266
DOI
10.1517/14712598.7.8.1257

Update on anti-CTLA-4 antibodies in clinical trials.

Breaking immune tolerance against tumor self-antigens is presently an area of intense research in the design of cancer therapies. One possible method to enhance immune system activation against tumor antigens is by blocking the inhibitory co-stimulatory signals mediated by cytotoxic T lymphocyte antigen 4, (CTLA-4) expressed on activated T cells. The fully human monoclonal antibodies that are directed against human CTLA-4, ipilimumab (Medarex/Bristol-Myers Squibb) and CP-675,206 (Pfizer/Abgenix, now Amgen), have demonstrated activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. They have also uncovered unusual immune-related adverse events manifesting as self-limiting inflammatory reactions of the bowel, skin and pituitary. This article reviews preclinical development and data generated from Phase I, II and III studies with regard to the end points reported and immune-related adverse events.

Authors
Langer, LF; Clay, TM; Morse, MA
MLA Citation
Langer, LF, Clay, TM, and Morse, MA. "Update on anti-CTLA-4 antibodies in clinical trials." Expert Opin Biol Ther 7.8 (August 2007): 1245-1256. (Review)
PMID
17696822
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
7
Issue
8
Publish Date
2007
Start Page
1245
End Page
1256
DOI
10.1517/14712598.7.8.1245

NCCN task force report: Management of patients with Gastrointestinal Stromal Tumor (GIST) - Update of the NCCN clinical practice guidelines

The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST. © Journal of the National Comprehensive Cancer Network 2007.

Authors
Demetri, GD; Benjamin, RS; Blanke, CD; Blay, JY; Casali, P; Choi, H; Corless, CL; Debiec-Rychter, M; DeMatteo, RP; Ettinger, DS; Fisher, GA; Fletcher, CDM; Gronchi, A; Hohenberger, P; Hughes, M; Joensuu, H; Judson, I; Le Cesne, A; Maki, RG; Morse, M; Pappo, AS; Pisters, PWT; Raut, CP; Reichardt, P; Tyler, DS; Van Den Abbeele, AD; Von Mehren, M; Wayne, JD; Zalcberg, J
MLA Citation
Demetri, GD, Benjamin, RS, Blanke, CD, Blay, JY, Casali, P, Choi, H, Corless, CL, Debiec-Rychter, M, DeMatteo, RP, Ettinger, DS, Fisher, GA, Fletcher, CDM, Gronchi, A, Hohenberger, P, Hughes, M, Joensuu, H, Judson, I, Le Cesne, A, Maki, RG, Morse, M, Pappo, AS, Pisters, PWT, Raut, CP, Reichardt, P, Tyler, DS, Van Den Abbeele, AD, Von Mehren, M, Wayne, JD, and Zalcberg, J. "NCCN task force report: Management of patients with Gastrointestinal Stromal Tumor (GIST) - Update of the NCCN clinical practice guidelines." JNCCN Journal of the National Comprehensive Cancer Network 5.SUPPL. 2 (July 20, 2007). (Review)
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
5
Issue
SUPPL. 2
Publish Date
2007

Investigation of HIFU-induced anti-tumor immunity in a murine tumor model.

BACKGROUND: High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment. METHODS: Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. In vivo dendritic cell activity was assessed along with the host's response to challenge tumor growth. RESULTS: Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-gamma-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio. CONCLUSION: These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to dendritic cell activation. Because DC activation was more pronounced when tumor cells were mechanically lysed by focused ultrasound treatment, mechanical HIFU in particular may be employed as a potential strategy in combination with subsequent thermal ablations for increasing the efficacy of HIFU cancer treatment by enhancing the host's anti-tumor immunity.

Authors
Hu, Z; Yang, XY; Liu, Y; Sankin, GN; Pua, EC; Morse, MA; Lyerly, HK; Clay, TM; Zhong, P
MLA Citation
Hu, Z, Yang, XY, Liu, Y, Sankin, GN, Pua, EC, Morse, MA, Lyerly, HK, Clay, TM, and Zhong, P. "Investigation of HIFU-induced anti-tumor immunity in a murine tumor model. (Published online)" J Transl Med 5 (July 11, 2007): 34-.
PMID
17625013
Source
pubmed
Published In
Journal of Translational Medicine
Volume
5
Publish Date
2007
Start Page
34
DOI
10.1186/1479-5876-5-34

NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines.

The NCCN Soft Tissue Sarcoma Guidelines include a subsection about treatment recommendations for gastrointestinal stromal tumors (GISTs). The standard of practice rapidly changed after the introduction of effective molecularly targeted therapy (such as imatinib and sunitinib) for GIST. Because of these changes, NCCN organized a multidisciplinary panel composed of experts in the fields of medical oncology, molecular diagnostics, pathology, radiation oncology, and surgery to discuss the optimal approach for the care of patients with GIST at all stages of the disease. The GIST Task Force is composed of NCCN faculty and other key experts from the United States, Europe, and Australia. The Task Force met for the first time in October 2003 and again in December 2006 with the purpose of expanding on the existing NCCN guidelines for gastrointestinal sarcomas and identifying areas of future research to optimize our understanding and treatment of GIST.

Authors
Demetri, GD; Benjamin, RS; Blanke, CD; Blay, J-Y; Casali, P; Choi, H; Corless, CL; Debiec-Rychter, M; DeMatteo, RP; Ettinger, DS; Fisher, GA; Fletcher, CDM; Gronchi, A; Hohenberger, P; Hughes, M; Joensuu, H; Judson, I; Le Cesne, A; Maki, RG; Morse, M; Pappo, AS; Pisters, PWT; Raut, CP; Reichardt, P; Tyler, DS; Van den Abbeele, AD; von Mehren, M; Wayne, JD; Zalcberg, J; NCCN Task Force,
MLA Citation
Demetri, GD, Benjamin, RS, Blanke, CD, Blay, J-Y, Casali, P, Choi, H, Corless, CL, Debiec-Rychter, M, DeMatteo, RP, Ettinger, DS, Fisher, GA, Fletcher, CDM, Gronchi, A, Hohenberger, P, Hughes, M, Joensuu, H, Judson, I, Le Cesne, A, Maki, RG, Morse, M, Pappo, AS, Pisters, PWT, Raut, CP, Reichardt, P, Tyler, DS, Van den Abbeele, AD, von Mehren, M, Wayne, JD, Zalcberg, J, and NCCN Task Force, . "NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines." J Natl Compr Canc Netw 5 Suppl 2 (July 2007): S1-29. (Review)
PMID
17624289
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
5 Suppl 2
Publish Date
2007
Start Page
S1
End Page
29

Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results.

PURPOSE: The overexpression of vascular endothelial growth factor (VEGF) is associated with poor outcomes in colorectal cancer patients. Bevacizumab, a VEGF inhibitor, enhances the effects of chemotherapy and radiation therapy on tumor cytotoxicity in preclinical models, including colorectal cancer. A Phase I trial was undertaken to evaluate the combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in patients with rectal cancer. METHODS AND MATERIALS: Patients with pathologically confirmed adenocarcinoma of the rectum were eligible. Pretreatment staging included computerized tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external beam radiation therapy (EBRT) to the tumor in 28 fractions. Capecitabine, oxaliplatin, and bevacizumab were administered concurrently with radiation therapy. After EBRT completion, patients were restaged and evaluated for surgery. Primary endpoints included the determination of dose-limiting toxicity and a recommended Phase II dose, non dose-limiting toxicity, and preliminary radiographic and pathologic response rates. RESULTS: Eleven patients were enrolled. All were evaluable for toxicity and efficacy. Dose level 2 was associated with unacceptable toxicity (primarily diarrhea). Dose level 1 had an acceptable toxicity profile. The recommended Phase II dose in our study was bevacizumab 15 mg/kg Day 1 + 10 mg/kg Days 8 and 22, oxaliplatin 50 mg/m2 weekly, and capecitabine 625 mg/m2 bid during radiation days. Six patients had clinical responses. Two patients had a pathologic complete response, and 3 had microscopic disease only. One patient experienced a postoperative abscess, one a syncopal episode during adjuvant chemotherapy, and one a subclinical myocardial infarction during adjuvant chemotherapy. CONCLUSIONS: The combination of bevacizumab, capecitabine, oxaliplatin, and radiation therapy in rectal cancer was tolerable, with encouraging response rates. Further investigation with this regimen is being pursued in a Phase II setting.

Authors
Czito, BG; Bendell, JC; Willett, CG; Morse, MA; Blobe, GC; Tyler, DS; Thomas, J; Ludwig, KA; Mantyh, CR; Ashton, J; Yu, D; Hurwitz, HI
MLA Citation
Czito, BG, Bendell, JC, Willett, CG, Morse, MA, Blobe, GC, Tyler, DS, Thomas, J, Ludwig, KA, Mantyh, CR, Ashton, J, Yu, D, and Hurwitz, HI. "Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results." Int J Radiat Oncol Biol Phys 68.2 (June 1, 2007): 472-478.
PMID
17498568
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
68
Issue
2
Publish Date
2007
Start Page
472
End Page
478
DOI
10.1016/j.ijrobp.2007.02.001

Dendritic cell vaccines.

Dendritic cells are antigen-presenting cells that have been shown to stimulate tumor antigen-specific T cell responses in preclinical studies. Consequently, there has been intense interest in developing dendritic cell based cancer vaccines. A variety of methods for generating dendritic cells, loading them with tumor antigens, and administering them to patients have been described. In recent years, a number of early phase clinical trials have been performed and have demonstrated the safety and feasibility of dendritic cell immunotherapies. A number of these trials have generated valuable preliminary data regarding the clinical and immunologic response to DC-based immunotherapy. The emphasis of dendritic cell immunotherapy research is increasingly shifting toward the development of strategies to increase the potency of dendritic cell vaccine preparations.

Authors
Mosca, PJ; Lyerly, HK; Clay, TM; Morse, MA; Lyerly, HK
MLA Citation
Mosca, PJ, Lyerly, HK, Clay, TM, Morse, MA, and Lyerly, HK. "Dendritic cell vaccines. (Published online)" Front Biosci 12 (May 1, 2007): 4050-4060. (Review)
PMID
17485358
Source
pubmed
Published In
Frontiers in bioscience : a journal and virtual library
Volume
12
Publish Date
2007
Start Page
4050
End Page
4060

Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy.

Two decades of research into the role of immunosuppression and angiogenesis in tumor biology have revealed multiple links between the two. Vascular endothelial growth factor, originally thought to be solely involved in vascular growth and permeability, has emerged as a significant agent of immune tolerance in the tumor microenvironment. This review examines two major elements of this field: the research behind the role of vascular endothelial growth factor in immunosuppression, especially as pertains to dendritic cell function; and the subsequent research into the potential for using antiangiogenic therapy to both starve tumors by hypoxia and enhance the response of tumors to immunotherapy. Several strategies tested so far have yielded incomplete, yet promising, results.

Authors
Johnson, BF; Clay, TM; Hobeika, AC; Lyerly, HK; Morse, MA
MLA Citation
Johnson, BF, Clay, TM, Hobeika, AC, Lyerly, HK, and Morse, MA. "Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy." Expert Opin Biol Ther 7.4 (April 2007): 449-460. (Review)
PMID
17373897
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
7
Issue
4
Publish Date
2007
Start Page
449
End Page
460
DOI
10.1517/14712598.7.4.449

A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma.

PURPOSE: Concurrent chemotherapy and radiation therapy (RT) are used to treat patients with esophageal cancer. The optimal combination of chemotherapeutic agents with RT is undefined. We evaluated a combination of capecitabine, carboplatin, and paclitaxel with RT in a phase I study. METHODS AND MATERIALS: Patients with squamous cell carcinoma or adenocarcinoma of the esophagus initially received capecitabine, carboplatin, and paclitaxel with RT (1.8 Gy daily to 50.4 Gy). After completion, patients were restaged and evaluated for surgery. Primary endpoints included determination of dose-limiting toxicities (DLT) and a recommended phase II dose, non-DLT, and preliminary radiographic and pathologic response rates. RESULTS: Thirteen patients were enrolled (10 men, 3 women). All were evaluable for toxicity and efficacy. Two of 3 patients at dose level 1 (capecitabine 825 mg/m(2) twice daily on RT days, carboplatin area under the curve (AUC) 2 weekly, paclitaxel 60 mg/m(2) weekly) had DLT (both Grade 4 esophagitis). Of these 3, 2 underwent esophagectomy and had pathologic complete response (pCR). Ten patients were then enrolled at dose level -1 (capecitabine 600 mg/m(2) twice daily, carboplatin AUC 1.5, paclitaxel 45 mg/m(2)). Overall, 3 of 10 patients at dose level -1 developed DLT (2 Grade 3 esophagitis, 1 Grade 3 hypotension). Esophagectomy was performed in 6 of 10 patients. All patients had pathologic downstaging and 2 of 6 had pCR. CONCLUSIONS: The maximally tolerated/recommended phase II doses were capecitabine 600 mg/m(2) twice daily, carboplatin AUC 1.5 weekly, and paclitaxel 45 mg/m(2) weekly with RT to 50.4 Gy. In our small study, this regimen appears active but is accompanied by significant toxicities, primarily esophagitis.

Authors
Czito, BG; Kelsey, CR; Hurwitz, HI; Willett, CG; Morse, MA; Blobe, GC; Fernando, NH; D'Amico, TA; Harpole, DH; Honeycutt, W; Yu, D; Bendell, JC
MLA Citation
Czito, BG, Kelsey, CR, Hurwitz, HI, Willett, CG, Morse, MA, Blobe, GC, Fernando, NH, D'Amico, TA, Harpole, DH, Honeycutt, W, Yu, D, and Bendell, JC. "A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma." Int J Radiat Oncol Biol Phys 67.4 (March 15, 2007): 1002-1007.
PMID
17197129
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
67
Issue
4
Publish Date
2007
Start Page
1002
End Page
1007
DOI
10.1016/j.ijrobp.2006.10.027

Resection of noncolorectal nonneuroendocrine liver metastases: a comparative analysis.

BACKGROUND: Although established for metastatic colorectal (CR) and neuroendocrine (NE) malignancies, the role of partial hepatectomy in management of metastases from other primaries (NCRNE) is not well-defined. STUDY DESIGN: The objective of this retrospective study is to compare outcomes after partial hepatectomy for NCRNE, NE, and CR metastases and to identify factors associated with longterm survival for patients with NCRNE diseases. Tumor characteristics, treatments, and outcomes of 360 consecutive patients undergoing resection of NCRNE (n = 82), CR (n = 245), and NE (n = 33) hepatic metastases from 1995 to 2005 were analyzed. NCRNE tumors included breast (n = 20), sarcomas (n = 19), genitourinary (n = 18), melanoma (n = 11), and other (n = 14) cancers. The start date for follow-up and survival analyses was the date of partial hepatectomy. RESULTS: For patients with NCRNE, CR, and NE tumors, there were no marked differences in postoperative mortality (4%, 4%, and 9%) or complication (30%, 42%, and 42%) rates. Median overall survival was longest for NE patients (not yet reached) versus NCRNE and CR (both 44 months) patients (p < 0.05, log-rank test). NCRNE patients had shorter disease-free survival than CR counterparts (13 versus 16 months), p < 0.05 (log-rank test). After median followup of 59 months for NCRNE patients, actuarial 5-year overall and disease-free survival was 37% and 16%, respectively, with 15 5-year survivors. Multivariable analysis suggests that interval from discovery of liver metastases to resection > 6 months (p = 0.08) and administration of chemoradiotherapy after resection (p = 0.06) might be associated with improved overall survival. CONCLUSIONS: In selected patients, resection of NCRNE liver metastases can be done safely with survival similar to CR metastases. Delay of liver resection for at least 6 months and treatment with chemoradiotherapy after resection might be associated with improved longterm survival after partial hepatectomy.

Authors
Reddy, SK; Barbas, AS; Marroquin, CE; Morse, MA; Kuo, PC; Clary, BM
MLA Citation
Reddy, SK, Barbas, AS, Marroquin, CE, Morse, MA, Kuo, PC, and Clary, BM. "Resection of noncolorectal nonneuroendocrine liver metastases: a comparative analysis." J Am Coll Surg 204.3 (March 2007): 372-382.
PMID
17324770
Source
pubmed
Published In
Journal of The American College of Surgeons
Volume
204
Issue
3
Publish Date
2007
Start Page
372
End Page
382
DOI
10.1016/j.jamcollsurg.2006.12.019

Immunotherapeutic targeting of Wilms' tumor protein.

The expression of Wilms' tumor protein (WT1)-derived peptides on malignant cell surfaces and recognition of those peptides by cellular and humoral immune responses suggest that WT1 may be a promising potential target antigen in immunotherapeutic trials. With a high frequency of expression in hematopoietic as well as solid tumors, WT1 is a broadly applicable target. Both in vivo mouse model and in vitro human studies have demonstrated the ability of WT1-specific cytotoxic T-lymphocytes to lyse WT1-expressing malignancies without harming normal tissue. WT1-peptide vaccination, in combination with adjuvants, has demonstrated the ability to activate WT1-specific immune responses and evidence of clinical activity. Because peptide-based vaccines are human leukocyte antigen-restricted, other more broadly applicable strategies are now being developed to activate WT1-specific immune responses, including the use of WT1-specific viral vectors.

Authors
Hutchings, Y; Osada, T; Woo, CY; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Hutchings, Y, Osada, T, Woo, CY, Clay, TM, Lyerly, HK, and Morse, MA. "Immunotherapeutic targeting of Wilms' tumor protein." Curr Opin Mol Ther 9.1 (February 2007): 62-69. (Review)
PMID
17330403
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
9
Issue
1
Publish Date
2007
Start Page
62
End Page
69

Natural killer cell activation and dendritic cell-based vaccines

Natural killer (NK) cells are the key players of the innate immune system, which can immediately limit or eliminate dangerous challenges by pathogens or tumor cells to the host. Recent studies have demonstrated the reciprocal activation of NK cell and dendritic cell (DC) through NK-DC interactions, elucidating the functional links between these two cell lineages. More details in NK-DC interactions, such as subsets of cells, molecular pathways involved and the possible anatomical sites, have been investigated and reported. Murine experiments have demonstrated that injection of mature DCs induces rapid recruitment of NK cells to lymph nodes, and that these NK cells provide interferon-γ(IFN-γ) for type 1 (Th1) priming of T cells. Thus, an increasing body of in vivo evidence is indicating that NK-DC interactions during the early phase of innate immunity can impact the quality and the magnitude of the subsequent adaptive immune response. Importantly, these studies imply that NK cells might not serve merely as cytotoxic effector cells combating virally-infected cells and malignant tumors, but might also play an important role as immunoregulatory cells with a significant influence on adaptive immunity. However, there is a relative paucity of information from the clinical side regarding NK cell function in adaptive immunity, as few DC vaccine studies have attempted to evaluate the antigen-nonspecific, yet potentially clinically-relevant, NK response to immunization. In this article, we will review studies focusing on NK-DC interactions and highlight the most recent clinical findings relating to the potential role of NK cells in DC-based vaccine therapy.

Authors
Osada, T; Clay, TM; Woo, CY; Morse, MA; Lyerly, HK
MLA Citation
Osada, T, Clay, TM, Woo, CY, Morse, MA, and Lyerly, HK. "Natural killer cell activation and dendritic cell-based vaccines." Minerva Biotecnologica 19.3 (2007): 91-104.
Source
scival
Published In
Minerva Biotecnologica
Volume
19
Issue
3
Publish Date
2007
Start Page
91
End Page
104

Learning from each other: Applying observations from anti-tumor, anti-pathogen and anti-toxin immunotherapy

Authors
Morse, MA; Whelan, M
MLA Citation
Morse, MA, and Whelan, M. "Learning from each other: Applying observations from anti-tumor, anti-pathogen and anti-toxin immunotherapy." Current Opinion in Molecular Therapeutics 9.1 (2007): 10-11.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
9
Issue
1
Publish Date
2007
Start Page
10
End Page
11

Concurrent chemoradiation for resectable extrahepatic cholangiocarcinoma

Authors
Nelson, JW; Willett, CG; Clough, R; Clary, BM; Pappas, TN; Tyler, DS; Bendell, JC; Hurwitz, HI; Morse, MA; Czito, BG
MLA Citation
Nelson, JW, Willett, CG, Clough, R, Clary, BM, Pappas, TN, Tyler, DS, Bendell, JC, Hurwitz, HI, Morse, MA, and Czito, BG. "Concurrent chemoradiation for resectable extrahepatic cholangiocarcinoma." 2007.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
69
Issue
3
Publish Date
2007
Start Page
S303
End Page
S303
DOI
10.1016/j.ijrobp.2007.07.1354

Quality measures for the use of adjuvant chemotherapy and radiation therapy in patients with colorectal cancer: a systematic review.

BACKGROUND: Chemotherapy (CT) and radiation therapy (RT) are essential components of adjuvant (preoperative or postoperative) therapy for many patients with colorectal cancer (CRC); however, quality measures (QMs) of these critical aspects of CRC treatment have not been characterized well. Therefore, the authors conducted a systematic review of the literature to determine the available QMs for adjuvant CT and RT in patients with CRC and rated their usefulness for assessing the delivery of quality care. METHODS: The MEDLINE and Cochrane data bases were searched for all publications that contained potential/actual QMs pertaining to adjuvant therapy for CRC. Identified QMs were rated by using criteria developed by the National Quality Forum. RESULTS: Thirty-two articles met the established inclusion/exclusion criteria. Those 32 articles contained 12 potential or actual QMs, 6 of which had major flaws that limited their applicability. The most useful QMs identified were 1) the percentage of patients with AJCC Stage III colon cancer who received postoperative CT and 2) the percentage of patients with Stage II or III rectal cancer who received chemoradiotherapy. CONCLUSIONS: To the authors' knowledge, very few QMs pertaining to adjuvant CT or RT for CRC have been published to date, and only half of those measures were rated as useful, acceptable, and valid in the current literature review. Future research should focus on refining existing QMs and on developing new QMs that target important leverage points with respect to the provision of adjuvant therapy for patients with CRC.

Authors
Prosnitz, RG; Patwardhan, MB; Samsa, GP; Mantyh, CR; Fisher, DA; McCrory, DC; Cline, KE; Gray, RN; Morse, MA
MLA Citation
Prosnitz, RG, Patwardhan, MB, Samsa, GP, Mantyh, CR, Fisher, DA, McCrory, DC, Cline, KE, Gray, RN, and Morse, MA. "Quality measures for the use of adjuvant chemotherapy and radiation therapy in patients with colorectal cancer: a systematic review." Cancer 107.10 (November 15, 2006): 2352-2360. (Review)
PMID
17039499
Source
pubmed
Published In
Cancer
Volume
107
Issue
10
Publish Date
2006
Start Page
2352
End Page
2360
DOI
10.1002/cncr.22278

Recent clinical progress in virus-based therapies for cancer.

As our knowledge of the molecular basis of cancer expands, viral vectors have been increasingly studied as potential antitumour therapeutic agents. With their ability to invade and replicate within target cells, viruses have been utilised as oncolytic agents to directly lyse tumour cells. Viruses can also deliver their genetic payload into infected cells, allowing for the repair of defective tumour suppressor genes, disruption of oncogenic pathways, and production of cytokines that activate the immune system. Finally, viruses encoding tumour-associated antigens can infect dendritic cells, triggering the development of a tumour-specific immune response. The ability to engineer viruses with high levels of tumour specificity and efficient rates of infection has enhanced the safety profile of these agents, allowing for the development of viable therapeutic options that have been examined in the clinic, either alone or in conjunction with more conventional therapies. This review highlights the principles underlying virus-based therapies for cancer, with an emphasis on recent developments from the clinic.

Authors
Woo, CY; Osada, T; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Woo, CY, Osada, T, Clay, TM, Lyerly, HK, and Morse, MA. "Recent clinical progress in virus-based therapies for cancer." Expert Opin Biol Ther 6.11 (November 2006): 1123-1134. (Review)
PMID
17049011
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
6
Issue
11
Publish Date
2006
Start Page
1123
End Page
1134
DOI
10.1517/14712598.6.11.1123

Gene therapy for lung cancer.

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer.

Authors
Toloza, EM; Morse, MA; Lyerly, HK
MLA Citation
Toloza, EM, Morse, MA, and Lyerly, HK. "Gene therapy for lung cancer." J Cell Biochem 99.1 (September 1, 2006): 1-22. (Review)
PMID
16767697
Source
pubmed
Published In
Journal of Cellular Biochemistry
Volume
99
Issue
1
Publish Date
2006
Start Page
1
End Page
22
DOI
10.1002/jcb.20851

Dendritic cell-based immunotherapy.

Dendritic cells (DCs) play a crucial role in the induction of antigen-specific T-cell responses, and therefore their use for the active immunotherapy of malignancies has been studied with considerable interest. More than a decade has passed since the publication of the first clinical data of DC-based vaccines, and through this and subsequent studies, a number of important developmental insights have been gleaned. These include the ideal source and type of DCs, the discovery of novel antigens and methods of loading DCs, the role of DC maturation, and the most efficient route of immunization. The generation of immune responses against tumor antigens after DC immunization has been demonstrated, and favorable clinical responses have been reported in some patients; however, it is difficult to pool the results as a whole, and thus the body of data remains inconclusive, in part because of varying DC preparation and vaccination protocols, the use of different forms of antigens, and, most importantly, a lack of rigorous criteria for defining clinical responses. As such, the standardization of clinical and immunologic criteria utilized, as well as DC preparations employed, will allow for the comparison of results across multiple clinical studies and is required in order for future trials to measure the true value and role of this treatment modality. In addition, issues regarding the optimal dose and clinical setting for the application of DC vaccines remain to be resolved, and recent clinical studies have been designed to begin to address these questions.

Authors
Osada, T; Clay, TM; Woo, CY; Morse, MA; Lyerly, HK
MLA Citation
Osada, T, Clay, TM, Woo, CY, Morse, MA, and Lyerly, HK. "Dendritic cell-based immunotherapy." Int Rev Immunol 25.5-6 (September 2006): 377-413. (Review)
PMID
17169781
Source
pubmed
Published In
International Reviews of Immunology (Informa)
Volume
25
Issue
5-6
Publish Date
2006
Start Page
377
End Page
413
DOI
10.1080/08830180600992456

NK cell activation by dendritic cell vaccine: a mechanism of action for clinical activity.

Recent reports revealed that dendritic cell (DC)-natural killer (NK) cell interaction plays an important role in tumor immunity, but few DC vaccine studies have attempted to evaluate the non-specific, yet potentially clinically relevant, NK response to immunization. In this study, we first analyzed in vitro activation of NK cells by DCs similar to those used in clinical trials. Subsequently, NK cell responses were analyzed in a phase I clinical trial of a vaccine consisting of autologous DCs loaded with a fowlpox vector encoding CEA. The data were compared with the clinical outcome of the patients. DC enhances NK activity in vitro, partly by sustaining NK cell survival and by enhancing the expression of NK-activating receptors, including NKp46 and NKG2D. Among nine patients in our clinical trial, NK cytolytic activity increased in four (range 2.5-5 times greater lytic activity) including three who had increased NK cell frequency, was stable in two and decreased in three. NKp46 and NKG2D expression showed a good correlation with the patients' NK activity. When patients were grouped by clinical activity (stable disease/no evidence of disease (stable/NE, n=5) vs progressive disease (N=4) at 3 months), the majority in the stable/NE group had increases in NK activity (P=0.016). Anti-CEA T cell response was enhanced in all the nine patients analyzed, but was not significantly different between the two groups (P=0.14). Thus, NK responses following DC vaccination may correlate more closely with clinical outcome than do T cell responses. Monitoring of NK response during vaccine studies should be routinely performed.

Authors
Osada, T; Clay, T; Hobeika, A; Lyerly, HK; Morse, MA
MLA Citation
Osada, T, Clay, T, Hobeika, A, Lyerly, HK, and Morse, MA. "NK cell activation by dendritic cell vaccine: a mechanism of action for clinical activity." Cancer Immunol Immunother 55.9 (September 2006): 1122-1131.
PMID
16273350
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
55
Issue
9
Publish Date
2006
Start Page
1122
End Page
1131
DOI
10.1007/s00262-005-0089-3

A phase I study of capecitabine (CAP), carboplatin (CARB), paclitaxel (TAX) and external beam radiation therapy (EBRT) for patients with esophageal carcinoma (EC).

14044 Background: Chemoradiotherapy is used to treat esophageal cancer with curative intent or local symptom control. A phase I study of 5-FU + CARB + TAX + EBRT showed 100% RR and 50% pCR rate. CAP allows for fluoropyrimidine treatment without the inconvenience of an infusion pump. CARB allows for platinum treatment with less toxicity than cisplatin. We evaluated this combination of agents in a phase I study.Patients with squamous cell carcinoma or adenocarcinoma of the esophagus requiring local therapy received CAP (825 mg/m2 bid on radiation days) + CARB (AUC 2 qweek) + TAX (60 mg/m2 qweek) + EBRT (1.8 Gy qd to 50.4 Gy). DLT was defined as any grade 4 heme toxicity, grade 3 heme toxicity lasting ≥ 7 days, ≥ grade 3 N/V, diarrhea, or esophagitis lasting ≥ 4 days despite optimal medical management, grade 3 other toxicity, inability to deliver 75% of scheduled CAP dose, or treatment delay > 3 days.13 pts were enrolled (10M, 3F). Median age was 62 (R- 48-78). EUS stage was uT3N0 (n=1), uT2N1 (n=1), or T3N1 (n=11). 2/3 pts had DLT at dose level 1 (both grade 4 esophagitis). Esophagectomy was performed in 2/3 patients, both pCR. Three pts were then enrolled at dose level -1 (CAP 600 mg/m2 bid + CARB AUC 1.5 + TAX 45 mg/m2). One patient developed DLT (grade 3 esophagitis) so 7 more pts were added at this dose level. Overall, 3/10 patients at dose level -1 developed DLT (two grade 3 esophagitis, one grade 3 hypotension). Esophagectomy was performed in 6/10 pts - 2/6 had pCR; 6/6 had pathologic downstaging.MTD for this regimen was CAP 625 mg/m2 bid + CARB AUC 1.5 + TAX 45 mg/m2 with EBRT to 50.4 Gy. However, at the MTD, this regimen is relatively toxic with no significant improvement in rate of pCR. [Table: see text].

Authors
Kelsey, CR; Czito, BG; Bendell, JC; Willett, CG; Morse, MA; D'Amico, TA; Honeycutt, W; Franklin, A; Yu, D; Hurwitz, HI
MLA Citation
Kelsey, CR, Czito, BG, Bendell, JC, Willett, CG, Morse, MA, D'Amico, TA, Honeycutt, W, Franklin, A, Yu, D, and Hurwitz, HI. "A phase I study of capecitabine (CAP), carboplatin (CARB), paclitaxel (TAX) and external beam radiation therapy (EBRT) for patients with esophageal carcinoma (EC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 24.18_suppl (June 2006): 14044-.
PMID
27952282
Source
epmc
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
14044

Cancer care quality measures: diagnosis and treatment of colorectal cancer.

OBJECTIVES: To identify measures that are currently available to assess the quality of care provided to patients with colorectal cancer (CRC), and to assess the extent to which these measures have been developed and tested. DATA SOURCES: Published and unpublished measures identified through a computerized search of English-language citations in MEDLINE (1966-January 2005), the Cochrane Database of Systematic Reviews, and the National Guideline Clearinghouse; through review of reference lists contained in seed articles, all included articles, and relevant review articles; and through searches of the grey literature (institutional or government reports, professional society documents, research papers, and other literature, in print or electronic format, not controlled by commercial publishing interests). Sources for grey literature included professional organization websites and the Internet. REVIEW METHODS: Measures were selected by reviewers according to standardized criteria relating to each question, and were then rated according to their importance and usability, scientific acceptability, and extent of testing; each domain was rated from 1 (poor) to 5 (ideal). RESULTS: We identified a number of well-developed and well-tested CRC-related quality-of-care measures, both general process-of-care measures (on a broader scale) and technical measures (pertaining to specific details of a procedure). At least some process measures are available for diagnostic imaging, staging, surgical therapy, adjuvant chemotherapy, adjuvant radiation therapy, and colonoscopic surveillance. Various technical measures were identified for quality of colonoscopy (e.g., cecal intubation rate, complications) and staging (adequate lymph node retrieval and evaluation). These technical measures were guideline-based and well developed, but less well tested, and the linkage between them and patient outcomes, although intuitive, was not always explicitly provided. For some elements of the care pathway, such as operative reports and chemotherapy reports, no technical measures were found. CONCLUSIONS: Some general process measures have a stronger evidence base than others. Those based on guidelines have the strongest evidence base; those derived from basic first principles supported by some research findings are relatively weaker, but are often sufficient for the task at hand. A consistent source of tension is the distinction between the clinically derived fine-tuning of the definition of a quality measure and the limitations of available data sources (which often do not contain sufficient information to act on such distinctions). Although some excellent technical measures were found, the overall development of technical measures seems less advanced than that of the general process measures.

Authors
Patwardhan, MB; Samsa, GP; McCrory, DC; Fisher, DA; Mantyh, CR; Morse, MA; Prosnitz, RG; Cline, KE; Gray, RN
MLA Citation
Patwardhan, MB, Samsa, GP, McCrory, DC, Fisher, DA, Mantyh, CR, Morse, MA, Prosnitz, RG, Cline, KE, and Gray, RN. "Cancer care quality measures: diagnosis and treatment of colorectal cancer." Evid Rep Technol Assess (Full Rep) 138 (May 2006): 1-116. (Review)
PMID
17764215
Source
pubmed
Published In
Evidence report/technology assessment
Issue
138
Publish Date
2006
Start Page
1
End Page
116

Supportive care in the management of colon cancer.

Patients with colorectal cancer present a number of supportive care challenges including those related to the underlying disease, such as gastrointestinal obstruction, nausea, anorexia, and fatigue, and those caused by the treatments, such as oral mucositis, neuropathy, and chemotherapy-induced diarrhea. Unique toxicities can accompany specific routes of administration of colon cancer drugs such as hand-foot syndrome with oral capecitabine and continuous infusion fluorouracil and biliary sclerosis with intrahepatic arterial floxuridine. The newer targeted therapies also present new toxicities, such as cardiovascular events and wound-healing complications with bevacizumab and rash and hypomagnesemia with cetuximab. Recent additions to the therapeutic armamentarium have presented new challenges, such as oxaliplatin-induced peripheral neuropathy, capecitabine-induced hand-foot syndrome, cetuximab-induced rash, and bevacizumab-associated arterial thrombotic events, bowel perforation, hypertension, and wound-healing complications. This article focuses on the prevention and management of several of these more common symptoms and toxicities.

Authors
Morse, MA
MLA Citation
Morse, MA. "Supportive care in the management of colon cancer." Support Cancer Ther 3.3 (April 1, 2006): 158-170.
PMID
18632490
Source
pubmed
Published In
Supportive cancer therapy
Volume
3
Issue
3
Publish Date
2006
Start Page
158
End Page
170
DOI
10.3816/SCT.2006.n.014

Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results.

PURPOSE: Overexpression of epidermal growth factor receptor (EGFR) has been associated with aggressive tumor phenotypes, chemotherapy, and radiation resistance, as well as poor survival in preclinical and clinical models. The EGFR inhibitor gefitinib potentiates chemotherapy and radiation tumor cytotoxicity in preclinical models, including pancreatic and colorectal cancer. We initiated two phase I trials assessing the combination of gefitinib, capecitabine, and radiation in patients with localized pancreatic and rectal cancer. PATIENTS AND METHODS: Patients with pathologically confirmed adenocarcinoma of the pancreas and rectum were eligible. Pretreatment staging included computed tomography, endoscopic ultrasound, and surgical evaluation. Patients received 50.4 Gy of external-beam radiation therapy to the tumor in 28 fractions. Capecitabine and gefitinib were administered throughout the radiation course. Following completion, patients were restaged and considered for resection. Primary end points included determination of dose-limiting toxicity (DLT) and a phase II dose; secondary end points included determination of non-DLTs and preliminary radiographic and pathologic response rates. RESULTS: Ten patients were entered in the pancreatic study and six in the rectal study. DLT was seen in six of 10 patients in the pancreatic study and two of six patients in the rectal study. The primary DLT in both studies was diarrhea. Two patients developed arterial thrombi. CONCLUSION: The combination of gefitinib, capecitabine, and radiation in pancreatic and rectal cancer patients resulted in significant toxicity. A recommended phase II dose was not determined in either of our studies. Further investigation with this combination should be approached with caution.

Authors
Czito, BG; Willett, CG; Bendell, JC; Morse, MA; Tyler, DS; Fernando, NH; Mantyh, CR; Blobe, GC; Honeycutt, W; Yu, D; Clary, BM; Pappas, TN; Ludwig, KA; Hurwitz, HI
MLA Citation
Czito, BG, Willett, CG, Bendell, JC, Morse, MA, Tyler, DS, Fernando, NH, Mantyh, CR, Blobe, GC, Honeycutt, W, Yu, D, Clary, BM, Pappas, TN, Ludwig, KA, and Hurwitz, HI. "Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results." J Clin Oncol 24.4 (February 1, 2006): 656-662.
PMID
16446337
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
4
Publish Date
2006
Start Page
656
End Page
662
DOI
10.1200/JCO.2005.04.1749

Role of natural killer cell function in dendritic cell-based vaccines.

Recent studies have elucidated the functional links between natural killer (NK) cells and, demonstrating the reciprocal activation of these cell types through NK-DC interactions. The subsets of cells and molecular pathways involved in such interactions have been defined, and the possible anatomical sites of these interactions have also been reported. Murine experiments have demonstrated that injection of mature DCs induces rapid recruitment of NK cells to lymph nodes and that these NK cells provide interferon-gamma for Type 1 priming. Thus, there is an increasing body of in vivo evidence indicating that NK-DC interactions during the early phase of innate immunity can impact the quality and magnitude of the subsequent adaptive immune response. Importantly, these studies imply that NK cells might not serve merely as cytotoxic lymphocytes combating viral pathogens and malignant tumors, but must also be considered as important immunoregulatory cells with a significant influence on adaptive immunity. In contrast to the large volume of knowledge obtained through basic research, there is a relative paucity of information regarding NK cell function in adaptive immunity from clinical trials, as few DC vaccine studies have attempted to evaluate the nonspecific, yet potentially clinically relevant, NK response to immunization. In this article, the authors will review studies focusing on NK-DC interactions and highlight the most recent clinical findings relating to the potential role of NK cells in DC-based vaccine therapy.

Authors
Woo, CY; Clay, TM; Lyerly, HK; Morse, MA; Osada, T
MLA Citation
Woo, CY, Clay, TM, Lyerly, HK, Morse, MA, and Osada, T. "Role of natural killer cell function in dendritic cell-based vaccines." Expert Rev Vaccines 5.1 (February 2006): 55-65. (Review)
PMID
16451108
Source
pubmed
Published In
Expert Review of Vaccines
Volume
5
Issue
1
Publish Date
2006
Start Page
55
End Page
65
DOI
10.1586/14760584.5.1.55

Fulfilling the promise of immunotherapy.

Authors
Bunce, C; Morse, MA
MLA Citation
Bunce, C, and Morse, MA. "Fulfilling the promise of immunotherapy." Curr Opin Mol Ther 8.1 (February 2006): 9-10. (Review)
PMID
16506519
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
8
Issue
1
Publish Date
2006
Start Page
9
End Page
10

A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract.

PURPOSE: Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase (DPD). It allows for oral dosing of 5-fluorouracil (5-FU), which may potentially improve the antitumor activity of 5-FU when delivered concurrently with radiotherapy while avoiding the inconvenience and morbidity of continuous infusion (CI) 5-FU. We addressed the safety of oral eniluracil/5-FU combined with radiation therapy and determined the profile of dose-limiting toxicities and recommended Phase II dose (RPTD) in patients with pancreatic and hepatobiliary cancers. METHODS AND MATERIALS: Patients with resectable or locally advanced pancreatic and biliary cancer received eniluracil (starting at 6.0 mg/m(2) q12h)/5-FU (starting at 0.6 mg/m(2) q12h). Eniluracil/5-FU were given concurrently with preoperative radiation to 4500 cGy followed by 540 cGy by reduced fields. Surgery was considered 4 weeks after completion of therapy. RESULTS: Thirteen patients were enrolled. Chemoradiotherapy was completed in all patients. The MTD was not reached and, thus, the RPTD of eniluracil/5-FU was determined to be 10 mg/m(2) q12h/1 mg/m(2) q12h. Two patients with locally advanced disease had a 30-45 percent cross-sectional tumor reduction, one of which underwent margin-negative resection. Two of 5 patients with pancreatic cancer, and 1 of 3 patients with cholangiocarcinoma, with underwent exploratory surgery had margin-negative resections. One patient had a pathologic complete response (pCR). Patient 5-FU plasma exposure increased slightly from Day 8 to Day 31. CONCLUSION: Preoperative chemoradiation with oral eniluracil/5-FU is feasible, well tolerated, and potentially effective in the neoadjuvant setting. Further investigation of oral fluoropyrimidines as radiosensitizers for pancreaticobiliary malignancies is warranted.

Authors
Czito, BG; Hong, TJ; Cohen, DP; Petros, WP; Tyler, DS; Pappas, TN; Yu, D; Lee, CG; Lockhart, AC; Morse, MA; Fernando, N; Hurwitz, HI
MLA Citation
Czito, BG, Hong, TJ, Cohen, DP, Petros, WP, Tyler, DS, Pappas, TN, Yu, D, Lee, CG, Lockhart, AC, Morse, MA, Fernando, N, and Hurwitz, HI. "A phase I study of eniluracil/5-FU in combination with radiation therapy for potentially resectable and/or unresectable cancer of the pancreas and distal biliary tract." Cancer Invest 24.1 (February 2006): 9-17.
PMID
16466986
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
24
Issue
1
Publish Date
2006
Start Page
9
End Page
17
DOI
10.1080/07357900500449454

Monitoring immunity to cancer vaccines

The potential use of vaccines to treat and prevent cancer has developed into an area of intense research. Great success has been achieved historically with vaccines against infectious agents, and observations such as a graft vs leukemia effect and spontaneous regression of tumors indicate the ability of the immune system to attack tumor cells. Vaccines are also an attractive option for cancer, because of the low level of side effects and complications compared with traditional cancer therapies. Further, vaccines can be combined with other immunomodulatory agents, such as cytokines and co-stimulatory factors, to further enhance the antitumor immune response.

Authors
Hobeika, AC; Clay, TM; Morse, MA
MLA Citation
Hobeika, AC, Clay, TM, and Morse, MA. "Monitoring immunity to cancer vaccines." Enhancer - Biotherapy of Cancer 4.2 (2006): 8-11.
Source
scival
Published In
Enhancer - Biotherapy of Cancer
Volume
4
Issue
2
Publish Date
2006
Start Page
8
End Page
11

Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

To determine whether HIFU treatment can elicit a systemic, anti-tumor immune response in vivo, MC-38 solid tumors grown subcutaneously at the right hindlimbs of C57BL/6 mice were treated in an experimental HIFU system. Three different treatment strategies that produce thermal, mechanical, or thermal combined with mechanical damage to the tumor tissue were evaluated. To detect anti-tumor immune response, a tumor challenge was performed on the left hindlimbs of the mice one day following the HIFU treatment, and subsequently, cytotoxic T lymphocyte (CTL) response was evaluated on day 14. All three HIFU treatment strategies were found to cause significant regression of the primary tumor, with the best suppressive effect produced by the thermal HIFU. In contrast, the most significant regression of the challenged tumor with concomitantly elevated CTL response were detected in mice treated by the mechanical HIFU, followed by the thermal combined with mechanical HIFU, but not in mice treated by the thermal HIFU alone. These findings suggest that alternative treatment strategies that promote mechanical lysis of the tumor cells (in contrast to purely thermal ablation) may enhance HIFU-induced anti-tumor immune response. © 2006 American Institute of Physics.

Authors
Hu, Z; Yang, XY; Liu, Y; Morse, MA; Lyerly, HK; Clay, TM; Zhong, P
MLA Citation
Hu, Z, Yang, XY, Liu, Y, Morse, MA, Lyerly, HK, Clay, TM, and Zhong, P. "Investigation of HIFU-induced anti-tumor immunity in a murine tumor model." AIP Conference Proceedings 829 (2006): 241-245.
Source
scival
Published In
AIP Conference Proceedings
Volume
829
Publish Date
2006
Start Page
241
End Page
245
DOI
10.1063/1.2205474

Immunization with fowlpox vector-modified dendritic cell in patients with carcinoembryonic antigen-expressing cancer: Phase I clinical study

A dendritic cell (DC), which can induce a primary immune response, is known to be the most potent antigen-presenting cell in the immune system. Many studies have been performed to evaluate the safety and efficacy of DC-based immunotherapy. At Duke University Medical Center, various methods of tumor antigen-loading to DC (i.e., peptide, protein, mRNA, virus vectors) were tried in patients with carcinoembryonic antigen (CEA)-expressing colorectal/lung cancers, HER2-expressing breast cancers, or prostate specific antigen (PSA)-expressing prostate cancers. In this article, we report the results of our latest study, a phase I clinical study of immunization with DCs modified with fowlpox vector encoding carcinoembryonic antigen and costimulatory molecules. We administered one or two cycles of four triweekly subcutaneous/intradermal injections of CEA-expressing DCs. Among the 14 patients enrolled (11 with colorectal cancer, 3 with non-small cell lung cancer), 12 patients completed at least one cycle of immunization. There were no immunization-related grade 3/4 toxicities. One patient showed a decrease in the CEA level and regression of the lymphadenopathy that occurred several months after completion of immunization. Five other patients were stable through at least one cycle of immunization. Immune monitoring assays showed induction of CEA-specific immune response in all immune responders. Thus, this vaccine strategy is safe, induces potent CEA-specific immune responses, and warrants further study.

Authors
Osada, T; Morse, MA
MLA Citation
Osada, T, and Morse, MA. "Immunization with fowlpox vector-modified dendritic cell in patients with carcinoembryonic antigen-expressing cancer: Phase I clinical study." Biotherapy 20.6 (2006): 541-548.
Source
scival
Published In
Biotherapy
Volume
20
Issue
6
Publish Date
2006
Start Page
541
End Page
548

Editorial overview: Fulfilling the promise of immunotherapy

Authors
Bunce, C; Morse, MA
MLA Citation
Bunce, C, and Morse, MA. "Editorial overview: Fulfilling the promise of immunotherapy." Current Opinion in Molecular Therapeutics 8.1 (2006): 9-10.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
8
Issue
1
Publish Date
2006
Start Page
9
End Page
10

A phase II study of active immunotherapy with PANVACTM or autologous, cultured dendritic cells infected with PANVACTM after complete resection of hepatic metastases of colorectal carcinoma

Authors
Lou, E; Marshall, J; Aklilu, M; Cole, D; Chang, D; Morse, M
MLA Citation
Lou, E, Marshall, J, Aklilu, M, Cole, D, Chang, D, and Morse, M. "A phase II study of active immunotherapy with PANVACTM or autologous, cultured dendritic cells infected with PANVACTM after complete resection of hepatic metastases of colorectal carcinoma." Clinical Colorectal Cancer 5.5 (2006): 368-371.
Source
scival
Published In
Clinical colorectal cancer
Volume
5
Issue
5
Publish Date
2006
Start Page
368
End Page
371
DOI
10.3816/CCC.2006.n.009

Adenocarcinoma of the duodenum: A 30-year experience

Authors
Nelson, JW; Kelsey, CR; Willett, CG; Tyler, DS; Pappas, TN; Hurwitz, HI; Bendell, JC; Morse, MA; Clough, R; Czito, BG
MLA Citation
Nelson, JW, Kelsey, CR, Willett, CG, Tyler, DS, Pappas, TN, Hurwitz, HI, Bendell, JC, Morse, MA, Clough, R, and Czito, BG. "Adenocarcinoma of the duodenum: A 30-year experience." 2006.
Source
wos-lite
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
66
Issue
3
Publish Date
2006
Start Page
S286
End Page
S286
DOI
10.1016/j.ijrobp.2006.07.540

Diagnosis of a solitary cardiac metastasis from ocular melanoma.

Authors
Chong, GT; Kim, RJ; Ambati, SR; Wong, TZ; Dibernardo, LR; Merkle, EM; Ryan, T; Morse, MA
MLA Citation
Chong, GT, Kim, RJ, Ambati, SR, Wong, TZ, Dibernardo, LR, Merkle, EM, Ryan, T, and Morse, MA. "Diagnosis of a solitary cardiac metastasis from ocular melanoma." J Thorac Cardiovasc Surg 130.6 (December 2005): 1727-1728.
PMID
16308029
Source
pubmed
Published In
Journal of Thoracic and Cardiovascular Surgery
Volume
130
Issue
6
Publish Date
2005
Start Page
1727
End Page
1728
DOI
10.1016/j.jtcvs.2005.07.058

Virus-based therapies for colon cancer.

Viral vectors are under development for anticancer therapy. As they can infect tumours and activate the immune system, viral vectors may directly destroy cancers (oncolysis), deliver genes with antitumour activity directly to the cancer cells, or act as cancer vaccines. Better insights into the biology of the various vectors in use (e.g., poxvectors, adenovirus, adeno-associated virus, reovirus, Newcastle disease virus) are making it possible to engineer viruses that are more tumour-specific, efficient at tumour infection, and which have enhanced safety due to incorporation of safeguards should dissemination occur. As considerable research has focused on therapy of colon cancer with viral vectors, this review will illustrate the major concepts of viral therapy of cancers with examples from studies targeting colorectal carcinoma.

Authors
Morse, MA
MLA Citation
Morse, MA. "Virus-based therapies for colon cancer." Expert Opin Biol Ther 5.12 (December 2005): 1627-1633. (Review)
PMID
16318426
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
5
Issue
12
Publish Date
2005
Start Page
1627
End Page
1633
DOI
10.1517/14712598.5.12.1627

Perspectives in colorectal cancer - Sixth Annual Conference. Metastatic colorectal cancer.

Authors
Morse, MA
MLA Citation
Morse, MA. "Perspectives in colorectal cancer - Sixth Annual Conference. Metastatic colorectal cancer." IDrugs 8.12 (December 2005): 974-977.
PMID
16320126
Source
pubmed
Published In
Idrugs
Volume
8
Issue
12
Publish Date
2005
Start Page
974
End Page
977

Combining cancer vaccines with chemotherapy.

Clinical experience is now demonstrating the efficacy of combining chemotherapy and targeted therapies. Although the combination of chemotherapy and immunotherapy would at first seem to be counterproductive, supportive preclinical and clinical data have revealed that cyclophosphamide, gemcitabine and doxorubicin enhance the efficacy of vaccines when used as a form of 'pretreatment'. Possible mechanisms of action include inhibition of regulatory T cells, enhancement of antigen presentation by tumours, or some yet unknown method. As such, more preclinical and clinical trials are needed to explore the synergistic effects of chemotherapy combined with immunotherapy, particularly the proper dose and timing of chemotherapy.

Authors
Chong, G; Morse, MA
MLA Citation
Chong, G, and Morse, MA. "Combining cancer vaccines with chemotherapy." Expert Opin Pharmacother 6.16 (December 2005): 2813-2820. (Review)
PMID
16318432
Source
pubmed
Published In
Expert Opinion on Pharmacotherapy
Volume
6
Issue
16
Publish Date
2005
Start Page
2813
End Page
2820
DOI
10.1517/14656566.6.16.2813

Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb.

Medarex and Bristol-Myers Squibb are developing ipilimumab, an immunostimulatory human antibody against cytotoxic T-lymphocyte antigen-4, for the potential combination or monotherapy treatment of melanoma, prostate, breast, renal and other cancers, as well as HIV infection.

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb." Curr Opin Mol Ther 7.6 (December 2005): 588-597.
PMID
16370382
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
7
Issue
6
Publish Date
2005
Start Page
588
End Page
597

Case 23-2005: a man with a mass in the liver.

Authors
Smith, AD; Morse, MA; Kuo, PC
MLA Citation
Smith, AD, Morse, MA, and Kuo, PC. "Case 23-2005: a man with a mass in the liver." N Engl J Med 353.20 (November 17, 2005): 2195-2197. (Letter)
PMID
16299939
Source
pubmed
Published In
The New England journal of medicine
Volume
353
Issue
20
Publish Date
2005
Start Page
2195
End Page
2197

Case 23-2005: A man with a mass in the liver

Authors
Smith, AD; Morse, MA; Kuo, PC
MLA Citation
Smith, AD, Morse, MA, and Kuo, PC. "Case 23-2005: A man with a mass in the liver." NEW ENGLAND JOURNAL OF MEDICINE 353.20 (November 17, 2005): 2196-2196.
Source
wos-lite
Published In
The New England journal of medicine
Volume
353
Issue
20
Publish Date
2005
Start Page
2196
End Page
2196

Release of endogenous danger signals from HIFU-treated tumor cells and their stimulatory effects on APCs.

The effects of high-intensity focused ultrasound (HIFU) on the release of endogenous danger signals from tumor cells and subsequent activation of antigen-presenting cells (APCs) were evaluated in vitro. MC-38 mouse tumor cells were treated using a 1.1 MHz HIFU transducer under two different protocols (P-=6.7 MPa, 30% duty cycle, 5 s vs. P-=10.7 MPa, 3% duty cycle, 30 s) to produce either thermal necrosis or mechanical lysis of the tumor cells. Here, we report that HIFU treatment can cause the release of endogenous danger signals (ATP and hsp60) and exposure of dendritic cells (DCs) and macrophages to the supernatants of HIFU-treated tumor cells leads to an increased expression of co-stimulatory molecules (CD80 and CD86) with enhanced secretion of IL-12 by the DCs and elevated secretion of TNF-alpha by the macrophages. The potency in APC activation produced by mechanical lysis is much stronger than thermal necrosis of the tumor cells. These findings suggest that optimization of treatment strategy may help to enhance HIFU-elicited anti-tumor immunity.

Authors
Hu, Z; Yang, XY; Liu, Y; Morse, MA; Lyerly, HK; Clay, TM; Zhong, P
MLA Citation
Hu, Z, Yang, XY, Liu, Y, Morse, MA, Lyerly, HK, Clay, TM, and Zhong, P. "Release of endogenous danger signals from HIFU-treated tumor cells and their stimulatory effects on APCs." Biochem Biophys Res Commun 335.1 (September 16, 2005): 124-131.
PMID
16055092
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
335
Issue
1
Publish Date
2005
Start Page
124
End Page
131
DOI
10.1016/j.bbrc.2005.07.071

Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs.

NKT cells can produce large amounts of both Th1- and Th2-type cytokines and are an important regulatory cell type. To elucidate their role in acquired immunity, we examined the effect of human Valpha24+Vbeta11+ NKT cells or CD1d-specific ligand alpha-galactosylceramide (alphaGalCer) on the in vitro generation of antigen-specific CTLs from PBMCs using autologous MART-1(26-35) peptide-pulsed dendritic cells as stimulators. Flow cytometry using tetramer for MART-1(26-35) peptide revealed that NKT cells have inhibitory effects on CTL generation. Cytokine analysis using cytometric bead array assay and ELISA showed higher IL-4 and IL-10 secretion in the alphaGalCer(+) and/or NKT cell(+) culture setting, whereas IL-13 secretion in the culture was not affected by the presence of alphaGalCer. The CD4+ NKT cell subset seemed to play a major role in this inhibitory effect by secreting large amounts of Th2-type cytokines. Interestingly however, unlike recent reports utilizing mouse models, IL-13 was not a main effector molecule in our human system. Culture with alphaGalCer in the presence of cytokine-neutralizing antibodies for the Th2 cytokines, IL-4, IL-5 and IL-10, resulted in enhanced CTL generation, suggesting the dominant role of Th2 cytokines over Th1 cytokines. Thus, CD4+ NKT cells can work as immunoregulatory T cells that suppress anti-tumor immune response and, therefore, NKT cells or alphaGalCer could be used as therapeutic modalities to modulate systemic immune responses, such as autoimmune diseases. Conversely, the use of NKT cells along with anti-Th2 cytokine-neutralizing antibodies or CD4-negative NKT cell subset could enhance the generation of antigen-specific CTLs for adoptive immunotherapy.

Authors
Osada, T; Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Osada, T, Morse, MA, Lyerly, HK, and Clay, TM. "Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs." Int Immunol 17.9 (September 2005): 1143-1155.
PMID
16027139
Source
pubmed
Published In
International Immunology
Volume
17
Issue
9
Publish Date
2005
Start Page
1143
End Page
1155
DOI
10.1093/intimm/dxh292

Adjuvant therapy of colon cancer: current status and future developments.

Options for the adjuvant therapy of resected stage III colon cancer have expanded beyond the previously well-accepted standard of 5-fluorouracil (5-FU) combined with leucovorin. The Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) study confirmed that capecitabine (Xeloda) is at least as effective and is less toxic than a bolus 5-FU and leucovorin regimen for patients with stage III colon cancer. This study, in addition to National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06, which demonstrated the equivalence of tegafur-uracil (UFT)/leucovorin with 5-FU/leucovorin, provides support for use of oral fluoropyrimidines for adjuvant therapy. Support for use of multiagent chemotherapy has been provided by the European MOSAIC study, which demonstrated a significant improvement in 3-year disease-free survival for the addition of oxaliplatin (Eloxatin) to infusional 5-FU and leucovorin (FOLFOX). Although adding irinotecan (Camptosar) to a bolus 5-FU and leucovorin regimen did not improve outcome in the adjuvant setting, the PETACC studies are evaluating the combination of infusional 5-FU, leucovorin, and irinotecan. In contrast to agreement on the appropriateness of therapy for stage III colon cancer, adjuvant therapy for patients with stage II disease remains controversial. Future advances in adjuvant therapy may include targeted therapies. Based on data demonstrating efficacy for the monoclonal antibodies bevacizumab (Avastin) and cetuximab (Erbitux) in the metastatic setting, clinical trials adding these agents to standard chemotherapy have been initiated in the adjuvant setting. Specifically, one U.S. cooperative group trial will evaluate the addition of bevacizumab to chemotherapy, a second will assess the addition of cetuximab, and a third trial will evaluate FOLFOX, infusional 5-FU/leucovorin (FOLFIRI), and FOLFOX followed by FOLFIRI. Finally, a study for patients with stage II disease and adverse prognostic factors will open. An important consideration in the new clinical trials is an assessment of molecular markers that either predict response or resistance to therapy or provide other prognostic information.

Authors
Morse, MA
MLA Citation
Morse, MA. "Adjuvant therapy of colon cancer: current status and future developments." Clin Colon Rectal Surg 18.3 (August 2005): 224-231.
PMID
20011305
Source
pubmed
Published In
Clinics in Colon and Rectal Surgery
Volume
18
Issue
3
Publish Date
2005
Start Page
224
End Page
231
DOI
10.1055/s-2005-916283

The development of therapeutic and preventive vaccines for gastric cancer and Helicobacter pylori.

Gastric cancer is one of the most important worldwide public health problems. Convincing epidemiologic and etiologic associations have been made between the development of gastric cancer and infection with Helicobacter pylori. H. pylori not only has adapted to survive within the harsh environment of the stomach but also is able to modulate and avoid endogenous immune responses. The design and creation of efficacious vaccine strategies against H. pylori requires an understanding of the complex interactions that make up mucosal immunity. An effective vaccine strategy against H. pylori has the potential to affect significantly on population health worldwide.

Authors
Chui, SY; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Chui, SY, Clay, TM, Lyerly, HK, and Morse, MA. "The development of therapeutic and preventive vaccines for gastric cancer and Helicobacter pylori." Cancer Epidemiol Biomarkers Prev 14.8 (August 2005): 1883-1889. (Review)
PMID
16103431
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
14
Issue
8
Publish Date
2005
Start Page
1883
End Page
1889
DOI
10.1158/1055-9965.EPI-04-0775

Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT.

BACKGROUND: Cryopreservation of PBMC and/or overnight shipping of samples are required for many clinical trials, despite their potentially adverse effects upon immune monitoring assays such as MHC-peptide tetramer staining, cytokine flow cytometry (CFC), and ELISPOT. In this study, we compared the performance of these assays on leukapheresed PBMC shipped overnight in medium versus cryopreserved PBMC from matched donors. RESULTS: Using CMV pp65 peptide pool stimulation or pp65 HLA-A2 tetramer staining, there was significant correlation between shipped and cryopreserved samples for each assay (p

Authors
Maecker, HT; Moon, J; Bhatia, S; Ghanekar, SA; Maino, VC; Payne, JK; Kuus-Reichel, K; Chang, JC; Summers, A; Clay, TM; Morse, MA; Lyerly, HK; DeLaRosa, C; Ankerst, DP; Disis, ML
MLA Citation
Maecker, HT, Moon, J, Bhatia, S, Ghanekar, SA, Maino, VC, Payne, JK, Kuus-Reichel, K, Chang, JC, Summers, A, Clay, TM, Morse, MA, Lyerly, HK, DeLaRosa, C, Ankerst, DP, and Disis, ML. "Impact of cryopreservation on tetramer, cytokine flow cytometry, and ELISPOT. (Published online)" BMC Immunol 6 (July 18, 2005): 17-.
PMID
16026627
Source
pubmed
Published In
BMC Immunology
Volume
6
Publish Date
2005
Start Page
17
DOI
10.1186/1471-2172-6-17

Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience.

PURPOSE: Primary adenocarcinoma of the gallbladder is a rare malignancy. To better define the role of adjuvant radiation therapy and chemotherapy, a retrospective analysis of the outcome of patients undergoing surgery and adjuvant therapy was undertaken. METHODS AND MATERIALS: Twenty-two patients with primary and nonmetastatic gallbladder cancer were treated with radiation therapy after surgical resection. Median radiation dose was 45 Gy. Eighteen patients received concurrent 5-fluorouracil (5-FU) chemotherapy. Median follow-up was 1.7 years in all patients and 3.9 years in survivors. RESULTS: The 5-year actuarial overall survival, disease-free survival, metastases-free survival, and local-regional control of all 22 patients were 37%, 33%, 36%, and 59%, respectively. Median survival for all patients was 1.9 years. CONCLUSION: Our series suggests that an approach of radical resection followed by external-beam radiation therapy with radiosensitizing 5-FU in patients with locally advanced, nonmetastatic carcinoma of the gallbladder may improve survival. This regimen should be considered in patients with resectable gallbladder carcinoma.

Authors
Czito, BG; Hurwitz, HI; Clough, RW; Tyler, DS; Morse, MA; Clary, BM; Pappas, TN; Fernando, NH; Willett, CG
MLA Citation
Czito, BG, Hurwitz, HI, Clough, RW, Tyler, DS, Morse, MA, Clary, BM, Pappas, TN, Fernando, NH, and Willett, CG. "Adjuvant external-beam radiotherapy with concurrent chemotherapy after resection of primary gallbladder carcinoma: a 23-year experience." Int J Radiat Oncol Biol Phys 62.4 (July 15, 2005): 1030-1034.
PMID
15990005
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
62
Issue
4
Publish Date
2005
Start Page
1030
End Page
1034
DOI
10.1016/j.ijrobp.2004.12.059

High-dose Allovectin-7 in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial.

Authors
Richards, JM; Bedikian, A; Gonzalez, R; Atkins, MB; Whitman, E; Lutzky, J; Morse, MA; Amatruda, T; Galanis, E; Thompson, J; Team, VCRO
MLA Citation
Richards, JM, Bedikian, A, Gonzalez, R, Atkins, MB, Whitman, E, Lutzky, J, Morse, MA, Amatruda, T, Galanis, E, Thompson, J, and Team, VCRO. "High-dose Allovectin-7 in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
720S
End Page
720S

Treatment of Ras mutation-bearing solid tumors using whole recombinant S. cerevisiae yeast expressing mutated Ras: Preliminary safety and immunogenicity results from a phase 1 trial.

Authors
Cohn, A; Morse, MA; O'Neil, B; Bellgrau, D; Duke, RC; Franzusoff, AJ; Munson, S; Ferraro, J; Rodell, TC
MLA Citation
Cohn, A, Morse, MA, O'Neil, B, Bellgrau, D, Duke, RC, Franzusoff, AJ, Munson, S, Ferraro, J, and Rodell, TC. "Treatment of Ras mutation-bearing solid tumors using whole recombinant S. cerevisiae yeast expressing mutated Ras: Preliminary safety and immunogenicity results from a phase 1 trial." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
183S
End Page
183S

High-dose Allovectin-7 in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial.

7543 Background: Allovectin-7, a bicistronic plasmid formulated with a cationic lipid system and encoding HLA-B7 and β-2 microglobulin, is an immunotherapeutic designed to induce a pro-inflammatory response and express allogenic MHC-class I antigen upon intralesional administration.We have conducted a Phase 2 dose-escalation trial to evaluate the safety and efficacy of Allovectin-7 in patients with metastatic melanoma. Eligible patients had stage III or IV metastatic melanoma recurrent or unresponsive to prior therapy; injectable lesion(s); ECOG PS 0-1 and adequate organ function. Patients with brain or visceral (except lung) metastases, abnormal LDH, or any lesion ≥100 cm(2) were excluded. Patients with 2 or more injectable lesions were randomized to receive injections of 2 mg Allovectin-7 divided for injection for up to 5 lesions. Patients received weekly intratumoral injections of a total of 2 mg of Allovectin-7 for 6 weeks followed by 3 weeks of observation and evaluation. Overall Response (OR) was assessed using RECIST guidelines two weeks following the last injection of each cycle. Patients with stable or responding disease received additional cycles of Allovectin-7.Final, audited data are presented for the 133 patients enrolled. All patients were evaluated for safety (6 patients in the dose-escalation stage and 127 patients in the 2 mg efficacy stage), and 127 patients were evaluated for efficacy. Fifteen patients (11.8%, 95% CI: 6.2-17.4) achieved an objective response lasting a median duration of 12.7 months (95% CI: 8.3 - ongoing). The responders include two patients who had lesions resected and found no evidence of melanoma. Median time to progression was 1.6 months and median overall survival was 21.3 months (95% CI: 14.8-33.4). There were no reported Grade 3 or Grade 4 adverse events associated with Allovectin-7.Results indicate that high-dose Allovectin-7 is an active, well-tolerated treatment for Stage III/IV metastatic melanoma patients with injectable cutaneous, subcutaneous, or nodal lesions. The details of the Phase 3, follow-up clinical trial design will be presented. [Table: see text].

Authors
Richards, JM; Bedikian, A; Gonzalez, R; Atkins, MB; Whitman, E; Lutzky, J; Morse, MA; Amatruda, T; Galanis, E; Thompson, J
MLA Citation
Richards, JM, Bedikian, A, Gonzalez, R, Atkins, MB, Whitman, E, Lutzky, J, Morse, MA, Amatruda, T, Galanis, E, and Thompson, J. "High-dose Allovectin-7 in patients with advanced metastatic melanoma: final phase 2 data and design of phase 3 registration trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 7543-.
PMID
27946003
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
7543

Treatment of Ras mutation-bearing solid tumors using whole recombinant S. cerevisiae yeast expressing mutated Ras: Preliminary safety and immunogenicity results from a phase 1 trial.

2571 Background: A number of tumors express activating, transforming mutations at codons 12 and 61 in the ras oncogene. We have previously shown that whole heat-inactivated recombinant S. cerevisiae expressing mutated Ras proteins induce protective cellular immunity as well as complete remission of established, carcinogen-induced, ras mutation-bearing lung tumors in mice (Cancer Res 64, 5084, 2004).GI-4014, GI-4015 and GI-4016 are recombinant yeast, each expressing a truncated and modified human Ras protein containing one of the three most common mutations at codon 12 (G12V, G12C, or G12D respectively) and the two most common mutations at codon 61 (Q61R and Q61L). In a four center Phase 1 trial, patients with advanced colorectal, pancreatic or non-small cell lung cancer, who have failed at least first line chemotherapy, have tumor samples subjected to genomic sequencing of the K-, H- and N-ras genes. If the tumor contains one of the target mutations, the subject receives 5 subcutaneous weekly doses of the corresponding product and is followed for an additional 56 days for safety, immunogenicity and tumor response.32 patients have been consented, of whom 9 had ras mutations in their tumors, 7 of which were contained in one of the three products. Six patients have been treated. Of 3 low-dose patients in whom cellular assay data are available, two have shown mutation-specific T cell responses by proliferation and cytokine secretion assays. No treatment-related serious adverse events have occurred and possibly treatment-related adverse events have been limited to mild fever and malaise in one subject.Recombinant yeast represent a novel vector for generating antigen-specific immune responses. Early data in humans suggest that, even at the lowest dose, these vectors generate mutation-specific cellular responses with an acceptable safety profile [Table: see text].

Authors
Cohn, A; Morse, MA; O'Neil, B; Bellgrau, D; Duke, RC; Franzusoff, AJ; Munson, S; Ferraro, J; Rodell, TC
MLA Citation
Cohn, A, Morse, MA, O'Neil, B, Bellgrau, D, Duke, RC, Franzusoff, AJ, Munson, S, Ferraro, J, and Rodell, TC. "Treatment of Ras mutation-bearing solid tumors using whole recombinant S. cerevisiae yeast expressing mutated Ras: Preliminary safety and immunogenicity results from a phase 1 trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 2571-.
PMID
27945865
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
2571

Successful desensitization to oxaliplatin.

OBJECTIVE: To report the successful desensitization of a patient to oxaliplatin utilizing an 8-hour desensitization regimen in a controlled environment. CASE SUMMARY: A 53-year-old white woman with metastatic colon cancer was receiving oxaliplatin, bevacizumab, and capecitabine every 2 weeks, with a partial response to therapy. On her fifth cycle of this regimen, she experienced diaphoresis, hypotension, nausea, abdominal cramping, and coryza. According to the Naranjo probability scale, oxaliplatin, and not bevacizumab, was the probable cause of the hypersensitivity reaction. The woman continued therapy with capecitabine and bevacizumab, resulting in stable disease. Due to her initial response to the oxaliplatin-based regimen, it was decided to attempt desensitization to oxaliplatin in a controlled, inpatient environment. An 8-hour desensitization schedule was employed, and the patient successfully completed an additional 3 cycles with full-dose oxaliplatin. DISCUSSION: Hypersensitivity reactions to platinum-containing compounds are well described and potentially life threatening. With expanded use of oxaliplatin in various malignancies, an increased number of hypersensitivity reactions will likely be reported. Patients with previous hypersensitivity reactions to carboplatin are at risk for similar reactions to oxaliplatin. We achieved successful desensitization for oxaliplatin using increased concentrations of the drug over an 8-hour period concomitant with oral and intravenous corticosteroids and histamine blockers. CONCLUSIONS: Hypersensitivity reactions to platinum compounds may result in discontinuation of active therapies in patients with metastatic disease. Desensitization to oxaliplatin is possible utilizing this approach.

Authors
Mis, L; Fernando, NH; Hurwitz, HI; Morse, MA
MLA Citation
Mis, L, Fernando, NH, Hurwitz, HI, and Morse, MA. "Successful desensitization to oxaliplatin." The Annals of pharmacotherapy 39.5 (May 2005): 966-969.
PMID
15784807
Source
epmc
Published In
The Annals of pharmacotherapy
Volume
39
Issue
5
Publish Date
2005
Start Page
966
End Page
969
DOI
10.1345/aph.1e532

Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.

PURPOSE: To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen. EXPERIMENTAL DESIGN: In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein. RESULTS: Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders. CONCLUSION: This immunization strategy is safe and activates potent CEA-specific immune responses.

Authors
Morse, MA; Clay, TM; Hobeika, AC; Osada, T; Khan, S; Chui, S; Niedzwiecki, D; Panicali, D; Schlom, J; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Hobeika, AC, Osada, T, Khan, S, Chui, S, Niedzwiecki, D, Panicali, D, Schlom, J, and Lyerly, HK. "Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules." Clin Cancer Res 11.8 (April 15, 2005): 3017-3024.
PMID
15837756
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
8
Publish Date
2005
Start Page
3017
End Page
3024
DOI
10.1158/1078-0432.CCR-04-2172

Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer.

BACKGROUND: Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. METHODS: Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods. RESULTS: The estimated overall survival (median +/- SE) in the entire group of patients undergoing resection was 23 +/- 4.2 months, with an estimated 3-year survival of 37% +/- 6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation. CONCLUSIONS: Histological response to neoadjuvant CRT--as measured by residual tumor load--may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.

Authors
White, RR; Xie, HB; Gottfried, MR; Czito, BG; Hurwitz, HI; Morse, MA; Blobe, GC; Paulson, EK; Baillie, J; Branch, MS; Jowell, PS; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Xie, HB, Gottfried, MR, Czito, BG, Hurwitz, HI, Morse, MA, Blobe, GC, Paulson, EK, Baillie, J, Branch, MS, Jowell, PS, Clary, BM, Pappas, TN, and Tyler, DS. "Significance of histological response to preoperative chemoradiotherapy for pancreatic cancer." Ann Surg Oncol 12.3 (March 2005): 214-221.
PMID
15827813
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
12
Issue
3
Publish Date
2005
Start Page
214
End Page
221
DOI
10.1245/ASO.2005.03.105

A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). METHODS: This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. RESULTS: Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1-2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52-665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. CONCLUSION: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors.

Authors
Morse, MA; Garst, J; Osada, T; Khan, S; Hobeika, A; Clay, TM; Valente, N; Shreeniwas, R; Sutton, MA; Delcayre, A; Hsu, D-H; Le Pecq, J-B; Lyerly, HK
MLA Citation
Morse, MA, Garst, J, Osada, T, Khan, S, Hobeika, A, Clay, TM, Valente, N, Shreeniwas, R, Sutton, MA, Delcayre, A, Hsu, D-H, Le Pecq, J-B, and Lyerly, HK. "A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. (Published online)" J Transl Med 3.1 (February 21, 2005): 9-.
PMID
15723705
Source
pubmed
Published In
Journal of Translational Medicine
Volume
3
Issue
1
Publish Date
2005
Start Page
9
DOI
10.1186/1479-5876-3-9

Recent developments in therapeutic cancer vaccines.

Therapeutic cancer vaccines are being developed with the intention of treating existing tumors or preventing tumor recurrence. While the results of clinical trials, predominantly in the metastatic setting have been sobering, the central hypothesis of active immunotherapy i.e. that the human immune system can be activated to recognize and destroy tumor cells, remains a viable one. We believe that a fundamental shift in how clinical trials are performed, and what concepts they test is required to make meaningful strides towards future clinical use of cancer vaccines. First, we must reappraise whether the metastatic setting is the appropriate arena to test these agents. Second, we must arrive at a consensus on the most important biologic endpoints and rapidly test vaccines for their ability to achieve these endpoints. Third, we need to expend more effort on understanding how to manipulate the immune system beyond the initial stimulation provided by a vaccine. Fourth, in order to permit comparison of results across different studies, it would be helpful to narrow down the large number of vaccine platforms. We will discuss the current state of development of cancer vaccines and the relevance for future clinical use of these agents to treat and prevent cancers.

Authors
Morse, MA; Chui, S; Hobeika, A; Lyerly, HK; Clay, T
MLA Citation
Morse, MA, Chui, S, Hobeika, A, Lyerly, HK, and Clay, T. "Recent developments in therapeutic cancer vaccines." Nat Clin Pract Oncol 2.2 (February 2005): 108-113. (Review)
PMID
16264883
Source
pubmed
Published In
Nature Clinical Practice Oncology
Volume
2
Issue
2
Publish Date
2005
Start Page
108
End Page
113
DOI
10.1038/ncponc0098

Enumerating antigen-specific T-cell responses in peripheral blood: a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis.

Detection of the circulating antigen-specific T-cell response to immunization is an important biologic end point in clinical trials of cancer vaccines. Typically employed assays are peptide MHC tetramer, ELISpot, and intracellular cytokine analysis. Although there is no agreement on the definition of a positive response in these assays, many groups have chosen a number of T cells greater than 2 standard deviations above the mean of the negative controls. The authors wished to determine how well this cutoff performed for each of these assays in detecting positive and negative T-cell responses to a model antigen, the immunodominant HLA-A*0201-restricted epitope of cytomegalovirus (CMV) pp65. For each assay, the mean + 2 standard deviations of the response for CMV seronegatives was the point that best separated the two groups. Using this value, each assay had a sensitivity of 87.5% and specificity of 95% to 100% and exhibited a high degree of concordance (kappa 0.76-0.9) with the other two. The authors conclude that currently available immunologic assays perform well in detecting biologically relevant levels of antigen-specific T cells. These assays will better define the quantity and quality of protective immune responses to viral disease and offer insight into the requirements for protective anti-cancer immunity.

Authors
Hobeika, AC; Morse, MA; Osada, T; Ghanayem, M; Niedzwiecki, D; Barrier, R; Lyerly, HK; Clay, TM
MLA Citation
Hobeika, AC, Morse, MA, Osada, T, Ghanayem, M, Niedzwiecki, D, Barrier, R, Lyerly, HK, and Clay, TM. "Enumerating antigen-specific T-cell responses in peripheral blood: a comparison of peptide MHC Tetramer, ELISpot, and intracellular cytokine analysis." J Immunother 28.1 (January 2005): 63-72.
PMID
15614046
Source
pubmed
Published In
Journal of Immunotherapy
Volume
28
Issue
1
Publish Date
2005
Start Page
63
End Page
72

Immune monitoring.

A wide array of immunologic tests are available for immune monitoring in cancer vaccine trials, and the number of novel assays and technical modifications continues to burgeon. Because only a small fraction of all proposed vaccine trials tested in phase I-II trials, for practical reasons, will ultimately move forward to be tested in phase III trials, there must be a system of establishing the most promising immunization strategies. This evaluation of cancer vaccine will require standardization of the immune assays and statistical methods used in immunologic monitoring. Furthermore, the use of a systematic approach to evaluating and adopting novel technologies for immunologic assessment would likely lead to timely implementation of more reliable, practical and cost-effective methods of immune. It should be the goal and expectation that this rational approach to immune monitoring will allow the critical appraisal of the most promising vaccine candidates in the context of pivotal, multi-center trials.

Authors
Mosca, PJ; Clay, TM; Morse, MA; Lyerly, HK
MLA Citation
Mosca, PJ, Clay, TM, Morse, MA, and Lyerly, HK. "Immune monitoring." Cancer Treat Res 123 (2005): 369-388. (Review)
PMID
16211879
Source
pubmed
Published In
Cancer Treatment and Research
Volume
123
Publish Date
2005
Start Page
369
End Page
388

Technology evaluation: Rexin-G, Epeius Biotechnologies

Rexin-G is a 'pathotropic', tumor-targeted, injectable retroviral vector carrying a mutant form of the cyclin G1 gene, under development by Epeius Biotechnologies for the potential treatment of metastatic cancer. The therapy is currently undergoing phase I/II clinical trials. © The Thomson Corporation.

Authors
Morse, M
MLA Citation
Morse, M. "Technology evaluation: Rexin-G, Epeius Biotechnologies." Current Opinion in Molecular Therapeutics 7.2 (2005): 164-169.
PMID
15844625
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
7
Issue
2
Publish Date
2005
Start Page
164
End Page
169

Immunotherapy of surgical malignancies: Commentary

Authors
Morse, MA; Lyerly, HK; Clay, TM
MLA Citation
Morse, MA, Lyerly, HK, and Clay, TM. "Immunotherapy of surgical malignancies: Commentary." Diseases of the Colon and Rectum 48.1 (2005): 182--.
Source
scival
Published In
Diseases of the Colon and Rectum
Volume
48
Issue
1
Publish Date
2005
Start Page
182-

Perspectives in Colorectal Cancer - Sixth Annual Conference. Metastatic colorectal cancer. 23-24 September 2005, Chicago, IL, USA

Authors
Morse, MA
MLA Citation
Morse, MA. "Perspectives in Colorectal Cancer - Sixth Annual Conference. Metastatic colorectal cancer. 23-24 September 2005, Chicago, IL, USA." IDrugs 8.12 (2005): 974-977.
Source
scival
Published In
Idrugs
Volume
8
Issue
12
Publish Date
2005
Start Page
974
End Page
977

Case 23-2005: A man with a mass in the liver [5] (multiple letters)

Authors
Hawkins, MA; Dawson, LA; Smith, AD; Morse, MA; Kuo, PC; Gans, H; Tanabe, KK; Chung, RT; Blaszkowsky, LS
MLA Citation
Hawkins, MA, Dawson, LA, Smith, AD, Morse, MA, Kuo, PC, Gans, H, Tanabe, KK, Chung, RT, and Blaszkowsky, LS. "Case 23-2005: A man with a mass in the liver [5] (multiple letters)." New England Journal of Medicine 353.20 (2005): 2195-2197.
PMID
16299940
Source
scival
Published In
The New England journal of medicine
Volume
353
Issue
20
Publish Date
2005
Start Page
2195
End Page
2197
DOI
10.1056/NEJM200511173532019

Editorial overview: What is a vaccine?

Authors
Bunce, C; Morse, MA
MLA Citation
Bunce, C, and Morse, MA. "Editorial overview: What is a vaccine?." Current Opinion in Molecular Therapeutics 7.1 (2005): 9-10.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
7
Issue
1
Publish Date
2005
Start Page
9
End Page
10

Intracellular Cytokine Assays

This chapter provides an overview of intracellular cytokine assays. Intracellular cytokine assays are a relatively new method of identifying cytokine production by individual T cells and have the ability to correlate cytokine expression with cell surface phenotype without cell separation. In addition, this highly sensitive flow cytometric method allows for the rapid detection of low frequency T cells expressing cytokine in response to specific antigen stimulation. The unique capabilities of this method make it a model assay for clinical and research applications. The overall premise of intracellular cytokine assays is direct detection of intracellular cytokine expression in response to antigen stimulation. Intracellular cytokine assays can be performed using various sources of cells and antigen depending on the target(s) of interest. T cell stimulation can be performed directly on whole blood, peripheral blood mononuclear cells, in vitro manipulated lymphocytes, isolated cells, and lymph nodes; although using whole blood for these assays provides a more physiological environment and may have an effect on the T cell response to stimulation. Since these assays are most often used to detect very low frequency events, appropriate control antigens are particularly important to ensure clear antigen specific response. © 2005 Elsevier Ltd. All rights reserved.

Authors
Hobeika, AC; Morse, MA; Clay, TM; Osada, T; Mosca, PJ; Lyerly, HK
MLA Citation
Hobeika, AC, Morse, MA, Clay, TM, Osada, T, Mosca, PJ, and Lyerly, HK. "Intracellular Cytokine Assays." 2005. 336-340.
Source
scival
Publish Date
2005
Start Page
336
End Page
340
DOI
10.1016/B978-012455900-4/50290-7

Regulatory and effector T cell subsets and dendritic cells in breast cancer.

Authors
Chui, SY; Morse, MA; Doldo, T; Osada, T; Clay, TM; Lyerly, HK; Khan, S; Gattis, A; Hobeika, AC
MLA Citation
Chui, SY, Morse, MA, Doldo, T, Osada, T, Clay, TM, Lyerly, HK, Khan, S, Gattis, A, and Hobeika, AC. "Regulatory and effector T cell subsets and dendritic cells in breast cancer." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
884S
End Page
884S

A phase 2 trial of high-dose allovectin-7 in patients with advanced metastatic melanoma.

Authors
Richards, J; Bedikian, AY; Gonzalez, R; Atkins, MB; Whitman, ED; Lutzky, J; Morse, MA; Amatruda, T; Galanis, E
MLA Citation
Richards, J, Bedikian, AY, Gonzalez, R, Atkins, MB, Whitman, ED, Lutzky, J, Morse, MA, Amatruda, T, and Galanis, E. "A phase 2 trial of high-dose allovectin-7 in patients with advanced metastatic melanoma." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
712S
End Page
712S

A phase I trial of a multi-epitope cancer vaccine (EP-2101) in non-small cell lung (NSCLC) and colon cancer patients.

Authors
Ishioka, GY; Disis, ML; Morse, MA; Cunningham, CC; Lenz, HJ; Figlin, RA; Chesnut, RW; Fikes, J
MLA Citation
Ishioka, GY, Disis, ML, Morse, MA, Cunningham, CC, Lenz, HJ, Figlin, RA, Chesnut, RW, and Fikes, J. "A phase I trial of a multi-epitope cancer vaccine (EP-2101) in non-small cell lung (NSCLC) and colon cancer patients." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
169S
End Page
169S

Regulatory and effector T cell subsets and dendritic cells in breast cancer.

9697 Background: Successful immune responses against breast cancer may depend on the balance between immune stimulation mediated through dendritic cells (DC) & cytolytic T cells, and immune inhibition mediated in part by CD4+CD25+ regulatory T cells (Treg) and CTLA4 expression on T cells. We hypothesized that low anti-tumor immunity in breast cancer patients might be partially explained by aberrations in the frequencies of these different components of the immune response compared with healthy individuals.We analyzed whole blood from 26 breast cancer patients (9 stage I, 8 stage II, 3 stage III, 6 stage IV) for Treg, DC subsets, CD8+CD45RA+CCR7- cytolytic effectors, and CTLA4 expressing T cells. Controls were 41 healthy volunteers.Breast cancer patients overall had higher levels of Treg (37+/-14% of CD4+ T cells) than controls (26.3 +/- 9%; p=0.002). Treg were higher in patients with stage II-IV disease, positive lymph nodes, and age < 65. Patients <65 also tended to have higher levels of CTLA4 on both CD4 and CD8+ T cells. Across all patients, there was a high positive correlation (0.82) of CTLA4 expression on Treg and CD8+ T cells, suggesting that the presence of this suppressive molecule may be a more generalized phenomenon in some individuals. The only groups that differed in CD8+CD45RA+CCR7- cytolytic effectors were premenopausal patients who had lower levels than post-menopausal women (37 vs 54%, p=0.04). Across all the patients, there was a modest negative correlation (-0.44) between Treg and CD8+ CD45RA+CCR7- suggesting that Treg may inhibit development of cytotoxic effector T cells. Finally, patients receiving chemotherapy and those with Stage IV disease had lower levels of immunostimulatory CD11c+ DC and higher levels of immunomodulatory CD123+ DC than other patients suggesting a possible negative impact of chemotherapy and advanced disease on stimulatory DC.This data highlights the inhibitory environment of the immune system in breast cancer patients, particularly those with advanced disease and younger age. Modification of this inhibitory environment will be needed to increase the activity of immunotherapy interventions in these patients. No significant financial relationships to disclose.

Authors
Chui, SY; Morse, MA; Doldo, T; Osada, T; Clay, TM; Lyerly, HK; Khan, S; Gattis, A; Hobeika, AC
MLA Citation
Chui, SY, Morse, MA, Doldo, T, Osada, T, Clay, TM, Lyerly, HK, Khan, S, Gattis, A, and Hobeika, AC. "Regulatory and effector T cell subsets and dendritic cells in breast cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 9697-.
PMID
28016077
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
9697

A phase I trial of a multi-epitope cancer vaccine (EP-2101) in non-small cell lung (NSCLC) and colon cancer patients.

2525 Background: Effective vaccines that mediate clinical responses in cancer patients may require generation of broadly specific cytotoxic T lymphocytes (CTLs) directed against multiple epitopes and tumor-associated antigens (TAAs). The EP-2101 vaccine was designed to induce CTLs against epitopes in carcinoembryonic antigen (CEA), p53, HER-2/neu, and MAGE 2/3, four TAAs frequently over-expressed in NSCLC and colon cancer. Using a rational epitope identification process, 2 epitopes from each TAA were selected for vaccine development. All 8 epitopes displayed high HLA-A2 supertype binding affinity and immunogenicity in a primary in vitro induction assay. Six of the epitopes were analogs containing a single substitution which either enhanced MHC binding or stimulated heteroclitic T cell activation, and 2 epitopes were native sequences. The 8 epitopes together with CAP1-6D, a previously described heteroclitic CEA analog, and the PADRE helper T cell epitope were emulsified in Montanide ISA51 adjuvant and tested for safety and immunogenicity in HLA-A2+ NSCLC (stage IIb/IIIa) and colon (stage III) cancer patients with no detectable disease following standard treatment.Patients received 6 EP-2101 treatments at 3 wk intervals, at a dose of 5 mg total peptide (0.5 mg/epitope). CTL responses in the peripheral blood of patients were measured using a validated interferon-gamma (IFN-γ) ELISPOT assay.Based on 7 patients who have completed treatment (4 colon, 3 lung), EP-2101 appears to be safe and well-tolerated. To date, IFN-γ-secreting CTL responses were observed in all three patients tested, with 1, 4, and 6 epitope responses being detected respectively. Vaccine responses against 1 native epitope and 5 analog epitopes in EP-2101 have ranged from 23-260 net spots/50,000 cells with <8 net spots detected in pre-vaccination samples.A cancer vaccine delivering 9 TAA epitopes can simultaneously induce CTL responses against multiple epitopes and TAAs in patients. This vaccine consisting of native and analog epitopes may provide effective immunotherapy in patients with diverse types of cancer expressing common TAAs. No significant financial relationships to disclose.

Authors
Ishioka, GY; Disis, ML; Morse, MA; Cunningham, CC; Lenz, HJ; Figlin, RA; Chesnut, RW; Fikes, J
MLA Citation
Ishioka, GY, Disis, ML, Morse, MA, Cunningham, CC, Lenz, HJ, Figlin, RA, Chesnut, RW, and Fikes, J. "A phase I trial of a multi-epitope cancer vaccine (EP-2101) in non-small cell lung (NSCLC) and colon cancer patients." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 2525-.
PMID
28015020
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
2525

A phase 2 trial of high-dose Allovectin-7 in patients with advanced metastatic melanoma.

7509 Background: A bicistronic plasmid encoding HLA-B7 and β-2 microglobulin genes formulated in cationic lipids, Allovectin-7® (A-7), is an immunotherapeutic designed to induce a pro-inflammatory response and express MHC-class I after tumor injections. Expression of HLA-B7 in tumors may result in increased immunorecognition of tumors that in turn elicits an antitumor response.We are conducting a phase 2 trial to evaluate the activity of A-7 in patients (pts) with metastatic melanoma (MM). Eligible pts have stage III or IV MM recurrent or unresponsive to prior therapy; injectable (1 to 25 cm2 cutaneous, subcutaneous, or nodal) lesion(s); ECOG PS 0-1 and adequate organ function. Pts with brain or non-lung visceral metastases or any lesion ≥ 100 cm2 are excluded. Pts with 2 or more injectable lesions are randomized to receive injections into 1 or up to 5 lesions. Pts receive weekly intratumoral injections of a total of 2 mg for 6 wks followed by 3 wks of observation and evaluation. Response is assessed using RECIST guidelines two wks following the last injection of each cycle. Pts with stable or responding disease receive additional cycles.Interim unaudited data will be presented for all 133 pts enrolled. All pts were evaluated for safety (6 pts in the dose escalation stage plus 127 pts in the high-dose stage), and 127 pts are evaluated for efficacy. In an interim data analysis 12 of 91 pts (13.2%) achieved an objective response lasting a median duration of 6.4 months. Median overall survival has not yet been reached and durability of response is still accruing. One Grade 3 and no Grade 4 adverse event associated with A-7 have been reported.Interim results indicate that high-dose A-7 is an active, well-tolerated treatment for Stage III/IV MM pts with injectable cutaneous, subcutaneous, or nodal lesions. No significant financial relationships to disclose.

Authors
Richards, J; Bedikian, AY; Gonzalez, R; Atkins, MB; Whitman, ED; Lutzky, J; Morse, MA; Amatruda, T; Galanis, E
MLA Citation
Richards, J, Bedikian, AY, Gonzalez, R, Atkins, MB, Whitman, ED, Lutzky, J, Morse, MA, Amatruda, T, and Galanis, E. "A phase 2 trial of high-dose Allovectin-7 in patients with advanced metastatic melanoma." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 7509-.
PMID
28014899
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
7509

Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage.

BACKGROUND: It has been suggested that preoperative biliary drainage increases the risk of infectious complications of pancreaticoduodenectomy. AIMS: The aim of this study was to assess complications related to biliary stents/drains and postoperative morbidity in patients undergoing neoadjuvant chemoradiotherapy for periampullary cancer. PATIENTS: One hundred and eighty-four patients with periampullary neoplasms were prospectively selected for neoadjuvant external beam radiation therapy and 5-fluorouracil-based chemotherapy between 1995 and 2002. METHODS: The data were retrospectively completed and analysed with respect to biliary drainage, efficacy and complications of endoscopic biliary stents and postoperative morbidity. Patients who had undergone a surgical biliary bypass were excluded. RESULTS: Data were completed in 168 patients. One hundred and nineteen patients were treated with endoscopic biliary stents, 18 patients had a percutaneous biliary drain and 31 patients did not require biliary drainage. Hospitalisation for stent-related complications was necessary in 15% of the patients with endoscopic biliary stents. Seventy-two patients underwent pancreaticoduodenectomy. There was no significant difference in the rate of wound infections, intra-abdominal abscesses and overall complications between the groups with and without preoperative biliary drainage. CONCLUSIONS: Postoperative infectious complications are common in patients both with and without preoperative biliary drainage. A statistically significant difference in complication rates was not observed between these groups.

Authors
Gerke, H; White, R; Byrne, MF; Stiffier, H; Mitchell, RM; Hurwitz, HI; Morse, MA; Branch, MS; Jowell, PS; Czito, B; Clary, B; Pappas, TN; Tyler, DS; Baillie, J
MLA Citation
Gerke, H, White, R, Byrne, MF, Stiffier, H, Mitchell, RM, Hurwitz, HI, Morse, MA, Branch, MS, Jowell, PS, Czito, B, Clary, B, Pappas, TN, Tyler, DS, and Baillie, J. "Complications of pancreaticoduodenectomy after neoadjuvant chemoradiation in patients with and without preoperative biliary drainage." Dig Liver Dis 36.6 (June 2004): 412-418.
PMID
15248382
Source
pubmed
Published In
Digestive and Liver Disease
Volume
36
Issue
6
Publish Date
2004
Start Page
412
End Page
418

A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon.

PURPOSE: Eniluracil, an effective inactivator of dihydropyrimidine dehydrogenase, allows for oral dosing of 5-fluorouracil (5-FU), which avoids the morbidity of continuous infusion 5-FU. We addressed the safety of oral eniluracil and 5-FU combined with preoperative radiotherapy and determined the recommended Phase II dose and dose-limiting toxicity in patients with locally advanced rectal and colon cancer. METHODS AND MATERIALS: Patients with TNM Stage II or III rectal cancer and residual or recurrent colon cancer received eniluracil (starting at 6.0 mg/m(2) every 12 h) and 5-FU (starting at 0.6 mg/m(2) every 12 h). Eniluracil and 5-FU were given with a 5-week course of preoperative radiotherapy of 4500 cGy, with a possible 540-cGy boost. Surgery was performed approximately 4 weeks after completion of chemoradiotherapy. RESULTS: Twenty-two patients were enrolled; 1 patient was withdrawn owing to noncompliance. Chemotherapy was completed in all patients; radiotherapy was completed in 20 patients. The recommended Phase II dose of eniluracil and 5-FU was 8 mg/m(2) every 12 h and 0.8 mg/m(2) every 12 h, respectively. Diarrhea was the dose-limiting toxicity. Eleven of the 17 patients with primary rectal cancer underwent a sphincter-sparing procedure. One patient had a pathologic complete response. CONCLUSION: Preoperative chemoradiotherapy with oral eniluracil and 5-FU is feasible and well tolerated. Additional investigation is warranted.

Authors
Czito, BG; Hong, TJ; Cohen, DP; Tyler, DS; Lee, CG; Anscher, MS; Ludwig, KA; Seigler, HF; Mantyh, C; Morse, MA; Lockhart, AC; Petros, WP; Honeycutt, W; Spector, NL; Ertel, PJ; Mangum, SG; Hurwitz, HI
MLA Citation
Czito, BG, Hong, TJ, Cohen, DP, Tyler, DS, Lee, CG, Anscher, MS, Ludwig, KA, Seigler, HF, Mantyh, C, Morse, MA, Lockhart, AC, Petros, WP, Honeycutt, W, Spector, NL, Ertel, PJ, Mangum, SG, and Hurwitz, HI. "A Phase I trial of preoperative eniluracil plus 5-fluorouracil and radiation for locally advanced or unresectable adenocarcinoma of the rectum and colon." Int J Radiat Oncol Biol Phys 58.3 (March 1, 2004): 779-785.
PMID
14967434
Source
pubmed
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
58
Issue
3
Publish Date
2004
Start Page
779
End Page
785
DOI
10.1016/S0360-3016(03)01567-0

Effects of neoadjuvant chemoradiation on operative mortality and morbidity for pancreaticoduodenectomy

Authors
Cheng, TY; White, R; Ueno, T; Hurwitz, HI; Morse, MA; Czito, B; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
Cheng, TY, White, R, Ueno, T, Hurwitz, HI, Morse, MA, Czito, B, Clary, BM, Pappas, TN, and Tyler, DS. "Effects of neoadjuvant chemoradiation on operative mortality and morbidity for pancreaticoduodenectomy." February 2004.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
11
Issue
2
Publish Date
2004
Start Page
S54
End Page
S55
DOI
10.1007/BF02523980

Immunotherapy of surgical malignancies.

Authors
Morse, MA; Lyerly, HK; Clay, TM; Abdel-Wahab, O; Chui, SY; Garst, J; Gollob, J; Grossi, PM; Kalady, M; Mosca, PJ; Onaitis, M; Sampson, JH; Seigler, HF; Toloza, EM; Tyler, D; Vieweg, J; Yang, Y
MLA Citation
Morse, MA, Lyerly, HK, Clay, TM, Abdel-Wahab, O, Chui, SY, Garst, J, Gollob, J, Grossi, PM, Kalady, M, Mosca, PJ, Onaitis, M, Sampson, JH, Seigler, HF, Toloza, EM, Tyler, D, Vieweg, J, and Yang, Y. "Immunotherapy of surgical malignancies." Curr Probl Surg 41.1 (January 2004): 15-132. (Review)
PMID
14749625
Source
pubmed
Published In
Current Problems in Surgery
Volume
41
Issue
1
Publish Date
2004
Start Page
15
End Page
132
DOI
10.1016/S0011384003001321

How does the immune system attack cancer?

Authors
Morse, MA; Lyerly, HK; Clay, TM; Abdel-Wahab, O; Chui, SY; Garst, J; Gollob, J; Grossi, PM; Kalady, M; Mosca, PJ; Onaitis, M; Sampson, JH; Seigler, HF; Toloza, EM; Tyler, D; Vieweg, J; Yang, Y
MLA Citation
Morse, MA, Lyerly, HK, Clay, TM, Abdel-Wahab, O, Chui, SY, Garst, J, Gollob, J, Grossi, PM, Kalady, M, Mosca, PJ, Onaitis, M, Sampson, JH, Seigler, HF, Toloza, EM, Tyler, D, Vieweg, J, and Yang, Y. "How does the immune system attack cancer?." Current Problems in Surgery 41.1 (2004): 15-132.
Source
scival
Published In
Current Problems in Surgery
Volume
41
Issue
1
Publish Date
2004
Start Page
15
End Page
132
DOI
10.1016/j.cpsurg.2003.08.001

Active immunotherapy with Flt3-ligand mobilized peripheral blood dendritic cells loaded with carcinoembryonic antigen peptide in patients with metastatic malignancies

Background: Dendritic cells (DC) loaded with tumor antigens induce immune responses in some cancer patients. However, the most commonly used method for obtaining clinical grade DC requires in vitro generation over 7 days in media containing cytokine, increasing the complexity and cost of the cellular vaccine product. The cytokine Flt3-ligand (FL) increases peripheral blood DC numbers in humans permitting an alternative approach to obtaining an adequate number of clinical grade DCs. We sought to evaluate the safety and immunogenicity of immunizations with FL-mobilized DC loaded with the tumor antigen CEA. Methods: Patients with CEA-expressing cancers received FL 20 μg/kg/d SQ x 10 d and were then leukapheresed to obtain peripheral blood mononuclear cells enriched for DC (FL-DC). After maturation overnight, FL-DC were coadministered (1 × 107 cells) as a combined ID and SQ injection with a class I peptide fragment of CEA, hepatitis B core antigen, tetanus toxoid or KLH protein every 3 weeks for four immunizations. Results: We found that FL and FL-DC immunizations were well tolerated. Following FL, the CD11c+CD14- DC population within the PBMC increased (1.5 ± 1.4% to 8.5 ± 4.2%). After overnight maturation, 10 to 20% of these DC expressed the maturation marker CD80. Antigen-specific DTH reactivity was observed at injection sites in all but 1 patient. Antigen specific immune responses were detected in the peripheral blood of 4 of 6 patients by intracellular cytokine staining, ELISPOT, proliferation, or tetramer analysis. Among the 6 patients who completed the immunizations, there was 1 with stable disease and 5 with progressive disease. Immunization with mobilized dendritic cells loaded with tumor antigens appears feasible and induces low levels of immune response.

Authors
Morse, MA; Clay, TM; Hobeika, AC; Chui, S; Mosca, PJ; Caron, D; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Hobeika, AC, Chui, S, Mosca, PJ, Caron, D, and Lyerly, HK. "Active immunotherapy with Flt3-ligand mobilized peripheral blood dendritic cells loaded with carcinoembryonic antigen peptide in patients with metastatic malignancies." Journal of Applied Research 4.4 (2004): 554-569.
Source
scival
Published In
The journal of applied research
Volume
4
Issue
4
Publish Date
2004
Start Page
554
End Page
569

Flt3-ligand as a vaccine adjuvant: Results in a study of Flt3-ligand plus tetanus toxoid immunization

Dendritic cells (DC) efficiently process and present antigens to the effector arm of the immune system, thereby stimulating immunity against antigens of both foreign and self origin. Administration of Flt3-ligand (FL) has been reported to increase dendritic cell (DC) numbers in mice and humans. As a result, FL has attracted interest as an adjuvant for vaccine immunotherapy. To investigate whether FL might increase the immune response to a model recall antigen, we administered FL 25 μg/kg/d subcutaneously to six healthy volunteers followed by a standard injection of intramuscular tetanus toxoid (TT). A control cohort of six healthy volunteers received tetanus toxoid alone. Compared to subjects who received only TT, subjects who received Flt3L and TT had greater TT-specific DTH reactivity. In contrast, FL did not augment peripheral blood mononuclear cell proliferative responses or antibody responses to TT. FL resulted in inconsistent TT-specific T cell responses as measured by interferon-gamma ELISPOT and cytokine flow cytometry. We conclude that while FL mobilization of DC may enhance in vivo immune responses to a known immunogenic recall antigen, there are inconsistent effects on immune response detected by in vitro assays. Further study will be required to determine which individuals might experience augmentation of the immune response with FL.

Authors
Chui, S; Clay, TM; Mosca, PJ; Hobeika, AC; Osada, T; Galibert, L; Caron, D; Lyerly, HK; Morse, MA
MLA Citation
Chui, S, Clay, TM, Mosca, PJ, Hobeika, AC, Osada, T, Galibert, L, Caron, D, Lyerly, HK, and Morse, MA. "Flt3-ligand as a vaccine adjuvant: Results in a study of Flt3-ligand plus tetanus toxoid immunization." Journal of Applied Research 4.4 (2004): 536-549.
Source
scival
Published In
The journal of applied research
Volume
4
Issue
4
Publish Date
2004
Start Page
536
End Page
549

Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA.

BACKGROUND: Studies have suggested an increased risk of peritoneal seeding in patients with pancreatic cancer diagnosed by percutaneous FNA. EUS-FNA is an alternate method of diagnosis. The aim of this study was to compare the frequency of peritoneal carcinomatosis as a treatment failure pattern in patients with pancreatic cancer diagnosed by EUS-FNA vs. percutaneous FNA. METHODS: Retrospective review of patients with non-metastatic pancreatic cancer identified 46 patients in whom the diagnosis was made by EUS-FNA and 43 with the diagnosis established by percutaneous FNA. All had neoadjuvant chemoradiation. Patients underwent restaging CT after completion of therapy, followed by attempted surgical resection if there was no evidence of disease progression. RESULTS: There were no significant differences in tumor characteristics between the two study groups. In the EUS-FNA group, one patient had developed peritoneal carcinomatosis compared with 7 in the percutaneous FNA group (2.2% vs. 16.3%; p<0.025). No patient with a potentially resectable tumor in the EUS-FNA group had developed peritoneal carcinomatosis. CONCLUSIONS: Peritoneal carcinomatosis may occur more frequently in patients who undergo percutaneous FNA compared with those who have EUS-FNA for the diagnosis of pancreatic cancer. A concern for peritoneal seeding of pancreatic cancer via percutaneous FNA is warranted. EUS-guided FNA is recommended as the method of choice for diagnosis in patients with potentially resectable pancreatic cancer.

Authors
Micames, C; Jowell, PS; White, R; Paulson, E; Nelson, R; Morse, M; Hurwitz, H; Pappas, T; Tyler, D; McGrath, K
MLA Citation
Micames, C, Jowell, PS, White, R, Paulson, E, Nelson, R, Morse, M, Hurwitz, H, Pappas, T, Tyler, D, and McGrath, K. "Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA." Gastrointest Endosc 58.5 (November 2003): 690-695.
PMID
14595302
Source
pubmed
Published In
Gastrointestinal Endoscopy
Volume
58
Issue
5
Publish Date
2003
Start Page
690
End Page
695

Preparation of peptide-loaded dendritic cells for cancer immunotherapy.

Dendritic cell-based vaccines are being evaluated in clinical trials to determine their ability to activate clinically relevant tumor antigen-specific immune responses. Although some groups isolate dendritic cells from peripheral blood, most have found it more efficient to generate large numbers from peripheral blood progenitors, particularly plastic adherent or CD14+ monocytes, in media supplemented with GM-CSF and IL-4. These DC may then be matured, if desired, and loaded with antigen, such as tumor-associated peptides, prior to administration. We describe the scheme that we are currently using to generate peptide-loaded dendritic cells for our clinical trials of cancer immunotherapy.

Authors
Morse, MA; Clay, T; Colling, K; Lyerly, HK
MLA Citation
Morse, MA, Clay, T, Colling, K, and Lyerly, HK. "Preparation of peptide-loaded dendritic cells for cancer immunotherapy." Mol Biotechnol 25.1 (September 2003): 95-99.
PMID
13679640
Source
pubmed
Published In
Molecular Biotechnology
Volume
25
Issue
1
Publish Date
2003
Start Page
95
End Page
99
DOI
10.1385/MB:25:1:95

The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors.

Despite advancements in therapeutic regimens, the prognosis remains poor for patients with malignant gliomas. Specificity has been an elusive goal for current modalities, but immunotherapy has emerged as a potential means of designing more tumor-specific treatments. Dendritic cells (DC) are the specialized antigen presenting cells of the immune system and have served now as a platform for therapeutic immunizations against such cancers as lymphoma, multiple myeloma, melanoma, prostate cancer, renal cell carcinoma, non-small cell lung carcinoma, colon cancer, and even malignant gliomas. DC-based immunizations offer a number of advantages over traditional immunotherapeutic approaches to brain tumors, approaches that have proved promising despite concerns over central nervous system immune privilege and glioma-mediated immunosuppression. The future success of clinical trials will depend on the optimization and standardizing of procedures for DC generation, loading, and administration.

Authors
Fecci, PE; Mitchell, DA; Archer, GE; Morse, MA; Lyerly, HK; Bigner, DD; Sampson, JH
MLA Citation
Fecci, PE, Mitchell, DA, Archer, GE, Morse, MA, Lyerly, HK, Bigner, DD, and Sampson, JH. "The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors." J Neurooncol 64.1-2 (August 2003): 161-176. (Review)
PMID
12952297
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
64
Issue
1-2
Publish Date
2003
Start Page
161
End Page
176

Toward protecting the safety of participants in clinical trials.

It is a widely held belief that the current system of oversight of clinical research, particularly the means of assessing risks and minimizing harms to participants in clinical trials, could be improved. In particular, the system is inefficient with overemphasis on the monitoring ability of some groups such as research ethics review boards and investigators, underemphasis on others such as data monitoring committees (DMCs) and sponsors, confusion about responsibilities for safety and imperfect communication between these different groups. Research ethics review boards are not able to perform safety monitoring by review of individual adverse events and are often burdened by duplicative reviews of large multicenter studies. There are no standards for DMCs to ensure they can reliably identify safety issues. Sponsors may be overreliant on data audits and slow to disseminate safety data in a coherent summary. Investigators, their staffs and clinical sites may not fully appreciate all the nuances of good clinical practice or may be inattentive to the daily conduct of studies. Regulators, particularly those in the United States, have failed to completely harmonize their policies with each other or with international regulatory agencies. We recommend well-designed monitoring plans for all studies that are appropriate to their scope and risk, more centralized review of large multisite studies and closer local scrutiny of single-institution studies. In addition, sponsors should pay greater attention to monitoring adverse events and keeping up-to-date databases or investigator's brochures emphasizing safety issues. A minimal standard of education or expertise in good clinical practice should be established for investigators, their staffs and research ethics review board members. DMC composition and functions should be standardized and regulations should be harmonized nationally and internationally. Finally, there should be a concerted effort to study the efficacy of various components of the system.

Authors
Califf, RM; Morse, MA; Wittes, J; Goodman, SN; Nelson, DK; DeMets, DL; Iafrate, RP; Sugarman, J
MLA Citation
Califf, RM, Morse, MA, Wittes, J, Goodman, SN, Nelson, DK, DeMets, DL, Iafrate, RP, and Sugarman, J. "Toward protecting the safety of participants in clinical trials." Control Clin Trials 24.3 (June 2003): 256-271.
PMID
12757992
Source
pubmed
Published In
Controlled Clinical Trials
Volume
24
Issue
3
Publish Date
2003
Start Page
256
End Page
271

Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases.

OBJECTIVE: To examine survival and toxicity by querying a single-institutional experience with adjuvant hepatic arterial infusional (HAI) chemotherapy. SUMMARY BACKGROUND DATA: Three randomized series in the literature have examined adjuvant HAI after complete resection of liver metastases. Only one of these trials showed an overall survival benefit at 2 years but not over the entire time period of the study. Previous studies in patients with unresectable disease were plagued by high rates of biliary toxicity. METHODS: A retrospective review of a prospectively maintained database was performed. Hepatic arterial pumps were placed in the standard fashion. Patients received floxuridine at doses previously demonstrated as safe in the literature. Standard statistical methods were used. RESULTS: Twenty-one of 92 patients underwent placement of hepatic arterial pumps at the time of liver resection. The HAI group was similar in all demographic measures to the non-HAI group, with the exception that the HAI patients were significantly younger. No differences were seen between the groups in either disease-free or overall survival, although a trend toward improved hepatic progression-free survival was noted. Significant biliary sclerosis developed in six patients in the HAI group, requiring chronic indwelling stents in four patients. One patient died of progressive liver failure associated with this toxicity. CONCLUSIONS: Biliary toxicity is an important potential side effect of hepatic arterial chemotherapy. Although larger randomized studies and this one suggest significant improvements in hepatic recurrences, these have not reliably translated into overall survival benefit. This fact, in light of the potential toxicity, would argue for a larger confirmatory trial of HAI in the adjuvant setting, incorporating recent advances in systemic therapy and careful attention to hepatotoxicity.

Authors
Onaitis, M; Morse, M; Hurwitz, H; Cotton, P; Tyler, D; Clavien, P; Clary, B
MLA Citation
Onaitis, M, Morse, M, Hurwitz, H, Cotton, P, Tyler, D, Clavien, P, and Clary, B. "Adjuvant hepatic arterial chemotherapy following metastasectomy in patients with isolated liver metastases." Ann Surg 237.6 (June 2003): 782-788.
PMID
12796574
Source
pubmed
Published In
Annals of Surgery
Volume
237
Issue
6
Publish Date
2003
Start Page
782
End Page
788
DOI
10.1097/01.SLA.0000071561.76384.19

Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA.

Immunizations with dendritic cells (DC) transfected with RNA encoding tumor antigens induce potent tumor antigen-specific immune responses in vitro and in murine models. We performed a phase I study of patients with advanced carcinoembryonic antigen (CEA)-expressing malignancies followed by a phase II study of patients with resected hepatic metastases of colon cancer to assess safety and feasibility of administering autologous DC loaded with CEA mRNA. The immunizations were well tolerated. Of the 24 evaluable patients in the dose-escalation phase, there was 1 complete response (by tumor marker), 2 minor responses, 3 with stable disease, and 18 with progressive disease. In the phase II study, 9 of 13 patients have relapsed at a median of 122 days. Evidence of an immunologic response was demonstrated in biopsies of DC injection sites and peripheral blood of selected patients. We conclude that it is feasible and safe to administer mRNA-loaded DC to patients with advanced malignancies.

Authors
Morse, MA; Nair, SK; Mosca, PJ; Hobeika, AC; Clay, TM; Deng, Y; Boczkowski, D; Proia, A; Neidzwiecki, D; Clavien, P-A; Hurwitz, HI; Schlom, J; Gilboa, E; Lyerly, HK
MLA Citation
Morse, MA, Nair, SK, Mosca, PJ, Hobeika, AC, Clay, TM, Deng, Y, Boczkowski, D, Proia, A, Neidzwiecki, D, Clavien, P-A, Hurwitz, HI, Schlom, J, Gilboa, E, and Lyerly, HK. "Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA." Cancer Invest 21.3 (June 2003): 341-349.
PMID
12901279
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
21
Issue
3
Publish Date
2003
Start Page
341
End Page
349

De-novo cholangiocarcinoma in the setting of recurrent primary sclerosing cholangitis following liver transplant.

Orthotopic liver transplantation is the only definitive therapeutic option in patients with primary sclerosing cholangitis (PSC) and end-stage liver disease. However, PSC recurs in up to 20% of patients transplanted for this indication. To date, no patient has been reported to develop cholangiocarcinoma (CCA) post-transplant, without biliary tract cancer having been present pretransplant. Here, we report recurrent PSC complicated by de-novo CCA in a 31-year-old man transplanted for PSC 8 years earlier. Cholangiocarcinoma was confirmed using a combination of computed tomography, cholangiography, positron emission tomography and histological examination of biliary cytology. He has since been successfully re-transplanted following preoperative chemo-radiotherapy. No viable tumor was identified in the explanted liver. This case establishes that long-term complications associated with PSC and biliary-enteric surgery such as CCA may become apparent in new grafts post-transplant.

Authors
Heneghan, MA; Tuttle-Newhall, JE; Suhocki, PV; Muir, AJ; Morse, M; Bornstein, JD; Sylvestre, PB; Collins, B; Kuo, PC; Rockey, DC
MLA Citation
Heneghan, MA, Tuttle-Newhall, JE, Suhocki, PV, Muir, AJ, Morse, M, Bornstein, JD, Sylvestre, PB, Collins, B, Kuo, PC, and Rockey, DC. "De-novo cholangiocarcinoma in the setting of recurrent primary sclerosing cholangitis following liver transplant." Am J Transplant 3.5 (May 2003): 634-638.
PMID
12752322
Source
pubmed
Published In
American Journal of Transplantation
Volume
3
Issue
5
Publish Date
2003
Start Page
634
End Page
638

Current status of dendritic cell immunotherapy of malignancies.

Because dendritic cells (DC) are central to the induction of antigen-specific T cell responses, their use for the active immunotherapy of malignancies has been of considerable interest. Since clinical trials with DC-based vaccines have been initiated, a number of important developmental issues have become apparent. These include the ideal source and type of DC, the form of antigen and method of loading DC, whether to induce maturation, the route and timing of immunization, and the optimal clinical scenario. Clinical responses such as stability of disease and tumor regressions have been reported in some patients, particularly with melanoma, myeloma, and prostate cancer.

Authors
Mosca, PJ; Clay, TM; Kim Lyerly, H; Morse, MA
MLA Citation
Mosca, PJ, Clay, TM, Kim Lyerly, H, and Morse, MA. "Current status of dendritic cell immunotherapy of malignancies." Int Rev Immunol 22.3-4 (May 2003): 255-281. (Review)
PMID
12745642
Source
pubmed
Published In
International Reviews of Immunology (Informa)
Volume
22
Issue
3-4
Publish Date
2003
Start Page
255
End Page
281

Comparison of antigen-specific T cell responses induced by transduction of human dendritic cells with E1- and E1-, E2b- adenoviral vectors: Development of adenovirus vectors for DC-based anti-tumor immunotherapy

Authors
Venturi, CB; Osada, T; Serraz, D; Hartman, Z; Evelyn, C; Morse, MA; Clay, TM; Amalfitano, A; Lyerly, HK
MLA Citation
Venturi, CB, Osada, T, Serraz, D, Hartman, Z, Evelyn, C, Morse, MA, Clay, TM, Amalfitano, A, and Lyerly, HK. "Comparison of antigen-specific T cell responses induced by transduction of human dendritic cells with E1- and E1-, E2b- adenoviral vectors: Development of adenovirus vectors for DC-based anti-tumor immunotherapy." April 14, 2003.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
17
Issue
7
Publish Date
2003
Start Page
C331
End Page
C331

Suppression of antigen-specific CTL generation by human NKT cell secretion of TH2 cytokines

Authors
Osada, T; Morse, MA; Clay, TM; Shimosaka, A; Lyerly, HK
MLA Citation
Osada, T, Morse, MA, Clay, TM, Shimosaka, A, and Lyerly, HK. "Suppression of antigen-specific CTL generation by human NKT cell secretion of TH2 cytokines." April 14, 2003.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
17
Issue
7
Publish Date
2003
Start Page
C77
End Page
C78

A need for effective adjuvants.

Authors
Bunce, CJ; Morse, MA
MLA Citation
Bunce, CJ, and Morse, MA. "A need for effective adjuvants." Curr Opin Mol Ther 5.1 (February 2003): 8-9.
PMID
12669464
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
5
Issue
1
Publish Date
2003
Start Page
8
End Page
9

HER2 dendritic cell vaccines.

HER2/neu, a tumor antigen overexpressed by a third of breast cancers, is a potential target for vaccine therapies. A particularly potent immunization strategy to induce T-cell responses against tumor antigens is to use dendritic cells (DCs) loaded with the tumor antigen. We performed two small studies to test the safety, feasibility, and immunologic and clinical responses to immunizations with in vitro-generated DCs loaded with either a human leukocyte antigen A2-restricted peptide fragment of the extracellular domain of the tumor antigen HER2 (E75) or a HER2 intracellular domain (ICD) protein in patients with high-risk resected breast cancer or metastatic cancers expressing HER2. There were no toxicities due to the immunizations in any of the patients. In the study of DCs loaded with the E75 peptide, 1 of 6 patients with metastatic HER2-expressing malignancies who completed all immunizations had stable disease for 6 months; the remainder of the patients had progressive disease. Delayed-type hypersensitivity (DTH) reactivity (2-3 mm of induration) at E75-loaded DC injection sites was observed in 2 of 5 patients evaluated but was similar at the unloaded DC injection sites. In 2 patients, the DTH sites underwent biopsy and a perivascular infiltrate of CD4 and CD8 cells was demonstrated, which was greater in the E75-loaded DC injection sites than in the unloaded DC sites. In the pilot study of ICD-loaded DC in patients with high-risk resected breast cancer, all 3 patients enrolled had no evidence of recurrence at a follow-up of up to 2.5 years. Intracellular domain-specific T-cell responses were detected directly from the peripheral blood by enzyme-linked immunospot and proliferation assay in 2 patients. We conclude that it is feasible and safe to generate and administer HER2-loaded DCs to patients with advanced HER2/neu-expressing malignancies and high-risk breast cancer. The magnitude of the immune responses generated is fairly modest, and more potent DC loading and maturation strategies will be necessary to optimize these vaccines.

Authors
Morse, MA; Clay, TM; Colling, K; Hobeika, A; Grabstein, K; Cheever, MA; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Colling, K, Hobeika, A, Grabstein, K, Cheever, MA, and Lyerly, HK. "HER2 dendritic cell vaccines." Clin Breast Cancer 3 Suppl 4 (February 2003): S164-S172.
PMID
12620155
Source
pubmed
Published In
Clinical Breast Cancer
Volume
3 Suppl 4
Publish Date
2003
Start Page
S164
End Page
S172

Proteomics for monitoring immune responses to cancer vaccines.

Standardized biomarkers for the detection of clinically significant immunological responses would be extremely valuable in immunotherapy trials. Most available assays measure either the frequency or function of antigen-specific T-cells, or the titers of antibodies or immune complexes. These assays have generally exhibited either inadequate sensitivity or too high a signal-to-noise ratio to reliably detect the low-frequency T-cell responses induced by cancer vaccines. In addition, such assays reflect only one aspect of the immune response rather than the complete picture. Proteomics, the study of proteins within a cell or biological sample, may offer a novel approach to immunological monitoring that complements existing immunological assays. By studying the protein content of T-cells responding to a vaccine or in the serum of vaccinated individuals, it may be possible to develop a metric for quantitating the magnitude of immunological responses. Proteomics could also provide a tool for establishing the quality of the immune response and for obtaining valuable information regarding the underlying regulatory mechanisms and pathways. Advances in miniaturization and automation may also permit characterization of the immune response more rapidly and from smaller amounts of biological material than is possible with existing assay systems.

Authors
Mosca, PJ; Lyerly, HK; Ching, CD; Hobeika, AC; Clay, TM; Morse, MA
MLA Citation
Mosca, PJ, Lyerly, HK, Ching, CD, Hobeika, AC, Clay, TM, and Morse, MA. "Proteomics for monitoring immune responses to cancer vaccines." Curr Opin Mol Ther 5.1 (February 2003): 39-43. (Review)
PMID
12669469
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
5
Issue
1
Publish Date
2003
Start Page
39
End Page
43

Editorial overview - A need for effective adjuvants

Authors
Bunce, CJ; Morse, MA
MLA Citation
Bunce, CJ, and Morse, MA. "Editorial overview - A need for effective adjuvants." CURRENT OPINION IN MOLECULAR THERAPEUTICS 5.1 (February 2003): 8-9.
Source
wos-lite
Published In
Current Opinion in Molecular Therapeutics
Volume
5
Issue
1
Publish Date
2003
Start Page
8
End Page
9

Prognostic significance of histologic response to preoperative chemoradiation for periampullary tumors

Authors
White, R; Xie, HB; Gottfried, MR; Czito, BG; Hurwitz, HI; Morse, MA; Paulson, EK; Jowell, PS; Baillie, J; Branch, MS; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, R, Xie, HB, Gottfried, MR, Czito, BG, Hurwitz, HI, Morse, MA, Paulson, EK, Jowell, PS, Baillie, J, Branch, MS, Clary, BM, Pappas, TN, and Tyler, DS. "Prognostic significance of histologic response to preoperative chemoradiation for periampullary tumors." January 2003.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
10
Issue
1
Publish Date
2003
Start Page
S62
End Page
S62

Recent areas of development for dendritic cell vaccines.

Authors
Morse, MA; Chui, S; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Chui, S, Clay, TM, and Lyerly, HK. "Recent areas of development for dendritic cell vaccines." Cancer Chemother Biol Response Modif 21 (2003): 339-350. (Review)
PMID
15338754
Source
pubmed
Published In
Cancer chemotherapy and biological response modifiers
Volume
21
Publish Date
2003
Start Page
339
End Page
350

Establishment of a nude mouse model of hepatic metastasis for evaluation of targeted retroviral gene delivery: Commentary

Authors
Morse, M; Clary, B; Lyerly, HK
MLA Citation
Morse, M, Clary, B, and Lyerly, HK. "Establishment of a nude mouse model of hepatic metastasis for evaluation of targeted retroviral gene delivery: Commentary." Journal of Surgical Oncology 82.2 (2003): 131--.
Source
scival
Published In
Journal of Surgical Oncology
Volume
82
Issue
2
Publish Date
2003
Start Page
131-
DOI
10.1002/jso.10169

The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors

Authors
Fecci, PE; Mitchell, DA; Archer, GE; Morse, MA; Lyerly, HK; Bigner, DD; Sampson, JH
MLA Citation
Fecci, PE, Mitchell, DA, Archer, GE, Morse, MA, Lyerly, HK, Bigner, DD, and Sampson, JH. "The history, evolution, and clinical use of dendritic cell-based immunization strategies in the therapy of brain tumors." JOURNAL OF NEURO-ONCOLOGY 64.1 (2003): 161-176.
Source
wos-lite
Published In
Journal of Neuro-Oncology
Volume
64
Issue
1
Publish Date
2003
Start Page
161
End Page
176
DOI
10.1007/BF02700031

Dendritic cell-based vaccines in cancer: Clinical experience to date

Therapeutic vaccines that can activate the immune system to destroy malignancies hold the promise of a low-toxicity, precisely targeted anticancer treatment modality. Because dendritic cells (DCs) are central to the activation of antigen-specific immune responses, DCs loaded with tumor antigens are of considerable interest as therapeutic vaccines. Preclinical studies have demonstrated the potency of DC-based immunizations in promoting tumor rejection. Continued preclinical and clinical studies are assessing a number of important parameters regarding the formulation and administration regimen of DC-based vaccines and have provided support for phase I and II studies. Thus far, DC-mediated immunizations have been well tolerated, with few toxicities reported. Tumor regression has been reported in up to 30% of patients, particularly with immunologically sensitive tumors such as melanoma. Biologic activity, measured as activation of antigen-specific T cells, is reported in up to 100% of patients immunized against potent recall antigens, such as tetanus toxoid, and up to 30% of those immunized against tumor antigens. Current clinical trials are increasingly testing DC-based vaccines in patients with minimal residual disease, such as following attempted curative surgery or following high-dose chemotherapy and stem-cell support where clinical benefit is likely to be the greatest. Newer strategies are focusing on further modifications to DCs to increase their immunostimulatory potency. These include newer methods of antigen loading, better techniques for DC maturation, strategies to enhance polarization of DCs to ensure the induction of T helper cell type 1 immune responses, and the administration of adjunctive cytokines to augment the immune response following immunization.

Authors
Morse, MA; Mosca, PJ; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Mosca, PJ, Clay, TM, and Lyerly, HK. "Dendritic cell-based vaccines in cancer: Clinical experience to date." American Journal of Cancer 1.5 (December 1, 2002): 313-322. (Review)
Source
scopus
Published In
American Journal of Cancer
Volume
1
Issue
5
Publish Date
2002
Start Page
313
End Page
322
DOI
10.2165/00024669-200201050-00002

Immunoregulatory T cells in cancer immunotherapy.

Many of the tumour antigens targeted by active immunisation strategies are in fact self-antigens. Successful anticancer immunotherapy will therefore require not only potent methods of T cell activation, but also successful interference with mechanisms of immune tolerance that have evolved to prevent tissue destruction by autoreactive T cells. In addition to thymic deletion, anergy and skewing of T cell cytokine expression, a role for immunoregulatory T cells in the maintenance of self-tolerance has been suggested. Suppression of autoreactive T cells by regulatory T cells has been suggested to occur by both cytokine and cell-contact-dependent mechanisms. In murine models, suppression of auto-reactive T cells mediated by cell contact has been attributed to a population of spontaneously occurring CD4+CD25+ T cells. Cells with similar phenotype and function have been found in healthy humans. In murine models, these cells behave as regulatory T cells, counteracting autoimmune and inflammatory reactions, and have a role in tolerance and in peripheral T cell homeostasis. Of interest for cancer immunotherapy is the fact that depleting these cells results in the induction of antitumour immune responses, particularly after tumour specific vaccination. One hypothesis is that depleting these CD4+CD25+ counter-regulatory T cells in humans with cancer will enhance the efficacy of anticancer immunisations.

Authors
Morse, MA; Clay, TM; Mosca, P; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Mosca, P, and Lyerly, HK. "Immunoregulatory T cells in cancer immunotherapy." Expert Opin Biol Ther 2.8 (December 2002): 827-834. (Review)
PMID
12517262
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
2
Issue
8
Publish Date
2002
Start Page
827
End Page
834
DOI
10.1517/14712598.2.8.827

38th Annual Meeting of the American Society of Clinical Oncology. 18-21 May 2002, Orlando, Florida, USA.

The American Society of Clinical Oncology 38th Annual Meeting has continued to showcase an increasing number of biological and targeted therapies for the treatment of cancer and its complications. This review will provide an overview of the posters and presentations describing novel biological agents.

Authors
Morse, MA
MLA Citation
Morse, MA. "38th Annual Meeting of the American Society of Clinical Oncology. 18-21 May 2002, Orlando, Florida, USA." Expert Opin Emerg Drugs 7.2 (October 2002): 335-338.
PMID
15989555
Source
pubmed
Published In
Expert Opinion on Emerging Drugs
Volume
7
Issue
2
Publish Date
2002
Start Page
335
End Page
338
DOI
10.1517/14728214.7.2.335

Multiple signals are required for maturation of human dendritic cells mobilized in vivo with Flt3 ligand.

The ligand for the receptor tyrosine kinase fms-like tyrosine kinase 3 (Flt3L) is a growth factor for hematopoietic progenitors and induces expansion of the two distinct lineages of dendritic cells (DC) that have been described in humans. These two lineages, DC1 and DC2, have been described according to their ability to induce naive T cell differentiation to T helper cell type 1 (Th1) and Th2 effector cells, respectively. The immunoregulatory potential of DC1 and DC2 depends on their state of maturation and activation, which can be mediated by several molecules. Because monocyte-derived DC1 produce interleukin-12 (IL-12) when stimulated with CD40 ligand (CD40L), we hypothesized that similar results would be obtained with DC1 mobilized by Flt3L. Unexpectedly, we found that immature DC expanded in vivo by Flt3L treatment could not be stimulated to produce IL-12 in vitro using CD40L and/or interferon-gamma (IFN-gamma) alone. Instead, we found that Flt3L-mobilized DC from cancer patients require a sequence of specific signals for maturation, which included initial treatment with granulocyte macrophage-colony stimulating factor followed by a combination of maturation signals such as CD40L and IFN-gamma. Flt3L-mobilized DC matured in this manner possessed greater T cell-stimulatory function than nonmatured DC. The ability to generate phenotypically mature, IL-12-producing DC1 from peripheral blood mononuclear cells mobilized by Flt3L will have important implications for the development of effective cancer immunotherapy strategies.

Authors
Mosca, PJ; Hobeika, AC; Colling, K; Clay, TM; Thomas, EK; Caron, D; Lyerly, HK; Morse, MA
MLA Citation
Mosca, PJ, Hobeika, AC, Colling, K, Clay, TM, Thomas, EK, Caron, D, Lyerly, HK, and Morse, MA. "Multiple signals are required for maturation of human dendritic cells mobilized in vivo with Flt3 ligand." J Leukoc Biol 72.3 (September 2002): 546-553.
PMID
12223523
Source
pubmed
Published In
Journal of leukocyte biology
Volume
72
Issue
3
Publish Date
2002
Start Page
546
End Page
553

Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants.

Nonmyeloablative allogeneic stem cell transplantation (NMSCT) may destroy some malignancies through a graft-versus-tumor (GVT) effect, but tumor relapse and viral reactivation remain challenges for which immunizations may be helpful. Dendritic cells (DC), particularly DC1 and ex vivo-cultured DC, induce antigen-specific immune responses following viral infections and anti-tumor immunizations. DC2 may be tolerogenic. We hypothesize that successful immunizations following NMSCT will require adequate numbers of functional DC1 or ex vivo-generated DC. We determined the number, phenotype, and function of blood DC1 and DC2 and ex vivo-generated DC obtained from donor-recipient pairs before and up to 90 days after NMSCT. Although the percentage and number of recipient blood Lin(-) HLA-DR(+) CD11c(+) DC1 following NMSCT (median 0.46%, IQR 0.33-0.52%) was lower than donor DC1 (median 0.94%, IQR 0.40-2.2%) this was not significant. In contrast, the percentage and absolute number of blood Lin(-) HLA-DR(+) CD11c(-) CD123(+) DC2 was significantly decreased following the transplant (median 0.01% IQR 0.01-0.01% at day 60 compared with median 0.14%, IQR 0.10-0.38% for the donor before transplantation, p < 0.05). The yield (median 6.0%, IQR 5.5-8.5%) and allostimulatory function of ex vivo-generated DC did not differ significantly at any time point. The donor chimerism of blood and cultured DC reflected that of the overall white blood cells. Ex vivo-generated, donor DC loaded with cytomegalovirus (CMV) antigens were capable of stimulating a CMV-specific immune response in vitro within peripheral blood mononuclear cells of a patient following NMSCT. We conclude that blood DC numbers may be diminished following NMSCT transplant, but that DC1 recovery exceeds DC2 and functional DC may be generated from peripheral blood progenitors at all time points suggesting a possible use in immunization strategies.

Authors
Morse, MA; Rizzieri, D; Stenzel, TT; Hobeika, AC; Vredenburgh, JJ; Chao, NJ; Clay, TM; Mosca, PJ; Lyerly, HK
MLA Citation
Morse, MA, Rizzieri, D, Stenzel, TT, Hobeika, AC, Vredenburgh, JJ, Chao, NJ, Clay, TM, Mosca, PJ, and Lyerly, HK. "Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants." J Hematother Stem Cell Res 11.4 (August 2002): 659-668.
PMID
12201954
Source
pubmed
Published In
Journal of hematotherapy & stem cell research
Volume
11
Issue
4
Publish Date
2002
Start Page
659
End Page
668
DOI
10.1089/15258160260194802

DNA and RNA modified dendritic cell vaccines.

The purpose of this paper is to describe the strategies for genetic modification of dendritic cells for use in active immunotherapy for the treatment of malignancies. An accruing body of data supports the concept of directing a therapeutic immune response, mediated by the cellular arm of the immune system, against cancers in vivo. Dendritic cells are the most potent inducers of T cell-mediated immune responses against tumor-expressed antigens, by virtue of their ability to present tumor antigens in the context of major histocompatibility molecules to naïve T cells with receptors specific for the antigen. A variety of methods for directing antigens to the MHC molecules of dendritic cells and augmenting their T cell stimulatory activity have been developed. This paper describes one group of promising strategies, the genetic modification of dendritic cells to direct the expression of tumor antigens, costimulatory molecules, and stimulatory cytokines. Genetic modification can be effected by either DNA or RNA, and the genetic material may be delivered by vectors or by physical means. These approaches are now entering human clinical trials.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "DNA and RNA modified dendritic cell vaccines." World J Surg 26.7 (July 2002): 819-825. (Review)
PMID
11948364
Source
pubmed
Published In
World Journal of Surgery
Volume
26
Issue
7
Publish Date
2002
Start Page
819
End Page
825
DOI
10.1007/s00268-002-4058-0

Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF.

Treatment with myeloablative chemotherapy and autologous peripheral blood stem cell (PBSC) transplantation followed by vaccination with autologous dendritic cells (DCs) treated with tumor antigens is a promising therapeutic strategy for several types of cancer. Obtaining sufficient numbers of both PBSCs and DCs is central to this approach. Previously, it has been shown that administration of Flt-3-Ligand (FL) combined with either G-CSF or GM-CSF mobilizes large numbers of PBSCs in patients with cancer. In the current study, we sought to determine whether these same cytokines could simultaneously mobilize DCs into the PBSC leukapheresis collection. DCs were analysed in PBSC leukapheresis samples obtained from five patients with high-risk breast cancer who received G-CSF alone as priming prior to leukapheresis, four patients who received FL+G-CSF and five patients who received FL+GM-CSF. DCs were defined as cells with a lin(dim/-) HLA-DR+ CD11c+ phenotype. The proportions of DCs in the FL+G-CSF and FL+GM-CSF samples were significantly higher than in pre-mobilization peripheral blood and G-CSF leukapheresis samples. The mean yield of DCs/kg in the FL+GM-CSF samples was also significantly higher than the mean yield of DCs in the G-CSF samples. The FL+G-CSF and FL+GM-CSF mobilized DCs were immature by morphologic and phenotypic criteria but stimulated allogeneic T-cells at levels similar to DCs generated in culture from PBMCs. Overnight culture?of the immature DCs obtained from patients receiving either FL+G-CSF or FL+GM-CSF in TNF-alpha?resulted in the generation of mature DCs. In summary, administration of FL in combination with GM-CSF and G-CSF to patients with breast cancer can mobilize large numbers of immature DCs into PBSC leukapheresis collections.

Authors
Gasparetto, C; Gasparetto, M; Morse, M; Rooney, B; Vredenburgh, JJ; Long, GD; Rizzieri, DA; Loftis, J; Chao, NJ; Smith, C
MLA Citation
Gasparetto, C, Gasparetto, M, Morse, M, Rooney, B, Vredenburgh, JJ, Long, GD, Rizzieri, DA, Loftis, J, Chao, NJ, and Smith, C. "Mobilization of dendritic cells from patients with breast cancer into peripheral blood stem cell leukapheresis samples using Flt-3-Ligand and G-CSF or GM-CSF." Cytokine 18.1 (April 7, 2002): 8-19.
PMID
12090755
Source
pubmed
Published In
Cytokine
Volume
18
Issue
1
Publish Date
2002
Start Page
8
End Page
19

Redirecting cytotoxic T lymphocyte responses with T-cell receptor transgenes.

In cancer and viral diseases, a great deal of research has focused on generating T-cell responses that might prove therapeutic. These efforts stem from our understanding of the immune system. It is known that the natural immune response can protect or suppress some viral infections and it is hoped that a potent T-cell mediated immune response might also be harnessed to fight cancer. Immunotherapy is a particularly attractive candidate therapy for the treatment of metastatic cancer because of the immune systems capacity for body wide surveillance. Since the generation of T cell clones is a laborious task and it is often impossible to derive T cell clones of the desired specificity and function from many individuals, especially in a timely fashion required for therapeutic interventions, T-cell receptor (TCR) gene transfer has a lot of appeal. TCR gene transfer seeks to transfer the antigen specificity of a T cell clone to other T cells. This article will review the last 15 years of research in TCR gene transfer since the first successful TCR gene transfer experiment, and seeks to give an insight into the areas of investigation currently being pursued to improve on current results and move TCR gene transfer into the clinic.

Authors
Clay, TM; Morse, M; Lyerly, HK
MLA Citation
Clay, TM, Morse, M, and Lyerly, HK. "Redirecting cytotoxic T lymphocyte responses with T-cell receptor transgenes." Expert Opin Biol Ther 2.4 (April 2002): 353-360. (Review)
PMID
11955274
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
2
Issue
4
Publish Date
2002
Start Page
353
End Page
360
DOI
10.1517/14712598.2.4.353

Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells.

OBJECTIVE: To demonstrate the feasibility of inducing tumor antigen-specific immune responses in patients with metastatic cancer using total tumor RNA-loaded dendritic cells (DCs). SUMMARY BACKGROUND DATA: The authors have shown that DCs transfected with mRNA encoding defined tumor antigens induce tumor antigen-specific T-cell responses in vitro and in vivo. There may be significant advantages to inducing immune responses against the entire repertoire of antigens expressed by a patient's autologous tumor. METHODS: RNA was extracted from a metastatic colon cancer and used to load autologous DCs. The DCs were coincubated with autologous T cells and the cytolytic activity of the T cells was assessed by the ability to lyse the autologous tumor cells. RNA was then extracted from a metastatic lung cancer and used to load autologous DCs, followed by four injections of the DC vaccine given every 4 weeks. Tumor antigen-specific cytotoxic T lymphocyte activity was then evaluated by testing peripheral blood mononuclear cells for their ability to lyse an antigen-expressing target. RESULTS: DCs transfected with the total RNA content of autologous tumor cells stimulated antigen-specific T-cell responses that are capable of recognizing and lysing autologous, primary tumor cells in vitro. Tumor-specific immune responses were induced in a patient with a carcinoembryonic antigen-expressing adenocarcinoma after immunization with autologous DCs transfected with total tumor RNA. CONCLUSIONS: DCs transfected with total tumor RNA may represent a method for inducing immune responses against the entire repertoire of tumor antigens of surgically resected malignancies.

Authors
Nair, SK; Morse, M; Boczkowski, D; Cumming, RI; Vasovic, L; Gilboa, E; Lyerly, HK
MLA Citation
Nair, SK, Morse, M, Boczkowski, D, Cumming, RI, Vasovic, L, Gilboa, E, and Lyerly, HK. "Induction of tumor-specific cytotoxic T lymphocytes in cancer patients by autologous tumor RNA-transfected dendritic cells." Ann Surg 235.4 (April 2002): 540-549.
PMID
11923611
Source
pubmed
Published In
Annals of Surgery
Volume
235
Issue
4
Publish Date
2002
Start Page
540
End Page
549

Current status of adoptive immunotherapy of malignancies.

Adoptive immunotherapy involves the transfer of immune effectors with antitumour activity into the tumour bearing host. Early approaches such as lymphokine activator killer (LAK) cells and tumour infiltrating lymphocytes (TILs) have yielded occasional clinical responses. More recently, attempts to stimulate and/or select antigen-specific T-cells in vitro have demonstrated that tumour-specific adoptive immunotherapy is possible. These approaches require complicated and time consuming in vitro stimulation procedures. Therefore, genetic modification of bulk T-cell populations is an attempt to create a large population of T-cells with a single specificity. In addition to work being done to develop the most potent effector, other studies are working on improving T-cell trafficking to tumours and interfering with the tumour-induced immunosuppression that can impair in vivo T-cell activity.

Authors
Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, and Lyerly, HK. "Current status of adoptive immunotherapy of malignancies." Expert Opin Biol Ther 2.3 (March 2002): 237-247. (Review)
PMID
11890864
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
2
Issue
3
Publish Date
2002
Start Page
237
End Page
247
DOI
10.1517/14712598.2.3.237

Priming, boosting, measuring.

Authors
Bunce, CJ; Morse, MA
MLA Citation
Bunce, CJ, and Morse, MA. "Priming, boosting, measuring." Curr Opin Mol Ther 4.1 (February 2002): 13-14.
PMID
11883689
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
4
Issue
1
Publish Date
2002
Start Page
13
End Page
14

Cryosurgery after chemoembolization for hepatocellular carcinoma in patients with cirrhosis.

Most cirrhotic patients with hepatocellular carcinoma (HCC) are not candidates for resection. Transarterial chemoembolization (TACE) may ablate a significant portion of the tumor but has a high rate of recurrence. Cryosurgery may permit successful ablation of hepatic tumors but can be complicated by postoperative hemorrhage and is also associated with a significant risk of recurrence. The combination of the two techniques might be beneficial. We evaluated in a prospective study the safety and efficacy of this combination in cirrhotic patients with unresectable HCC. Fifteen patients were included in this study. All but one patient underwent one or several sessions of TACE before cryosurgery. Cryoablation was successfully performed in each patient. The patient who did not undergo preoperative TACE required reoperation for hemorrhage. Another patient with Child-Pugh class B cirrhosis died postoperatively of hepatic and multiorgan failure. At a mean follow-up of 2.5 years, three patients had recurrence of disease, and 13 of 15 patients were alive with the longest survival time being 5 years. The actuarial survival rate at 5 years was 79%. Cryosurgery after TACE is feasible in cirrhotic livers with HCC and can increase the cure rate in large tumors. TACE may reduce the risk of hemorrhage after cryosurgery but can increase the risk of hepatic failure in patients with poor hepatic function.

Authors
Clavien, PA; Kang, KJ; Selzner, N; Morse, MA; Suhocki, PV
MLA Citation
Clavien, PA, Kang, KJ, Selzner, N, Morse, MA, and Suhocki, PV. "Cryosurgery after chemoembolization for hepatocellular carcinoma in patients with cirrhosis." J Gastrointest Surg 6.1 (January 2002): 95-101.
PMID
11986024
Source
pubmed
Published In
Journal of Gastrointestinal Surgery
Volume
6
Issue
1
Publish Date
2002
Start Page
95
End Page
101

Dendritic cell maturation in active immunotherapy strategies.

Dendritic cells (DCs) loaded with tumour antigen have become the centrepiece of clinical trials testing active immunotherapy strategies. Important variables include the source of DCs, the choice of antigens, the method of antigen loading and the route and timing of administration. Recently, the requirement for and the method of, DC maturation have been receiving particular attention. This is due to observations from in vitro studies and animal models demonstrating that mature DCs induce more potent antigen-specific T-cells responses than immature DCs. Furthermore, preliminary observations in human studies suggest that immature DCs might actually downregulate antigen-specific T-cell responses but mature DCs may augment them. Current studies are addressing how to define DC maturation, whether the variety of methods for maturation result in DCs with similar T-cell stimulatory capacity, how to maintain the maturational status and whether maturation in vitro before immunisation, or in vivo, after immunisation, results in better DC function.

Authors
Morse, MA; Mosca, PJ; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Mosca, PJ, Clay, TM, and Lyerly, HK. "Dendritic cell maturation in active immunotherapy strategies." Expert Opin Biol Ther 2.1 (January 2002): 35-43. (Review)
PMID
11772338
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
2
Issue
1
Publish Date
2002
Start Page
35
End Page
43
DOI
10.1517/14712598.2.1.35

CEA loaded dendritic cell vaccines.

Authors
Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, and Lyerly, HK. "CEA loaded dendritic cell vaccines." Cancer Chemother Biol Response Modif 20 (2002): 385-390. (Review)
PMID
12703216
Source
pubmed
Published In
Cancer chemotherapy and biological response modifiers
Volume
20
Publish Date
2002
Start Page
385
End Page
390

The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer.

BACKGROUND: Resected pancreatic cancer has a high risk of recurrence and mortality despite the the use of chemoradiotherapy. Because pancreatic cancers express tumor antigens such as carcinoembryonic antigen (CEA), it may be possible to immunize patients to induce tumor antigen-specific immune responses. We hypothesize that high-frequency tumor antigen-specific immune responses will reduce recurrence and increase survival. Autologous dendritic cells (DCs) loaded with tumor antigens are particularly potent at inducing tumor antigen-specific immune responses. METHODS: Three patients with resected pancreatic adenocarcinoma following neoadjuvant chemoradiotherapy received autologous, monocyte-derived DCs loaded with the mRNA encoding CEA monthly for 6 mo. RESULTS: It was feasible to generate an adequate number of DC from these patients and to cryopreserve them for repeated use. The DC demonstrated the typical immature phenotype. The immunizations were well-tolerated without evidence of adverse events. All three developed injection site reactivity. All three are alive without evidence of disease at more than 2 1/2 yr from the original diagnosis. CONCLUSION: The postoperative period following neoadjuvant chemoradiotherapy and pancreaticoduodenectomy for pancreatic cancer is an ideal environment to test novel immune-based therapies. DC-based immunotherapy in this setting is safe and feasible and may lead to prolonged survival.

Authors
Morse, MA; Nair, SK; Boczkowski, D; Tyler, D; Hurwitz, HI; Proia, A; Clay, TM; Schlom, J; Gilboa, E; Lyerly, HK
MLA Citation
Morse, MA, Nair, SK, Boczkowski, D, Tyler, D, Hurwitz, HI, Proia, A, Clay, TM, Schlom, J, Gilboa, E, and Lyerly, HK. "The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer." Int J Gastrointest Cancer 32.1 (2002): 1-6.
PMID
12630764
Source
pubmed
Published In
International Journal of Gastrointestinal Cancer
Volume
32
Issue
1
Publish Date
2002
Start Page
1
End Page
6
DOI
10.1385/IJGC:32:1:1

Vaccines and gene therapy for colorectal cancer

Vaccination strategies against colorectal carcinoma attempt to stimulate and direct the body's endogenous immune defense mechanisms against growing malignancies. In similar manner, gene transfer technologies offer the potential to increase the immunogenicity of tumors, confer increased susceptibility to cytotoxic agents, interfere with tumor growth, and correct carcinogenic mutations. With progressive advances in the scientific understanding of carcinogenesis, immune regulation, and the manipulation of immune effector mechanisms at both cellular and molecular levels, vaccines and gene therapies for colon and rectal cancers are now entering preliminary human clinical trials. These novel approaches may eventually offer new treatment possibilities for patients with colorectal malignancies. Copyright 2002, Elsevier Science (USA). All rights reserved.

Authors
Chui, SY; Morse, MA
MLA Citation
Chui, SY, and Morse, MA. "Vaccines and gene therapy for colorectal cancer." Seminars in Colon and Rectal Surgery 13.4 (2002): 277-292.
Source
scival
Published In
Seminars in Colon and Rectal Surgery
Volume
13
Issue
4
Publish Date
2002
Start Page
277
End Page
292
DOI
10.1053/scrs.2002.127402

Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy

Background. Although resection is the sole chance of cure in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer to the liver, most patients are not candidates for surgery at the time of diagnosis. Strategies aiming at downstaging large or multifocal tumors to enable curative resection are appealing. The aim of this study was to evaluate the effects of neoadjuvant selective intra-arterial chemotherapy in noncirrhotic patients with unresectable HCC or metastatic colorectal cancer to the liver in the absence of extrahepatic disease. Methods. Selective chemotherapy was provided by using a subcutaneous pump device via a catheter placed in the gastroduodenal artery. Chemotherapy regimen included floxuridine (0.2 mg/kg/day for 14 days) in each patient with additional boluses of cisplatin and doxorubicin on day 1 of each cycle in the presence of HCC. Patients were evaluated at 3, 6, 9, and 12 months for possible curative resection. Complete follow-up was available for each patient. Results. Twenty-eight patients with unresectable liver tumors (5 HCC and 23 metastatic colorectal cancer) were included in this study. There were no surgical complications related to pump insertion, and local chemotherapy was started within 1 week of surgery in each patient. The median follow-up in survivors was 31 months (range, 30 months to 5 years). Chemotherapy was well tolerated in 18 (64 %) patients. Chemotherapy was discontinued in 4 patients because of abnormal liver function test results, and 2 of them required a biliary stent to relieve a biliary stricture. In 9 patients downstaging enabled curative resection (3 HCC, 6 colorectal metastasis). Seven of these patients were alive and tumor free at the completion of the study, with at least 2 years of follow-up. The actuarial survival rates at 3 years for HCC and colorectal metastases were 60% and 50%, respectively. Conclusions. About one third of patients with unresectable liver tumors can be successfully treated by neoadjuvant intra-arterial chemotherapy followed by curative resection. This strategy appears particularly, promising in patients with large HCC. This approach should be investigated further.

Authors
Clavien, P-A; Selzner, N; Morse, M; Selzner, M; Paulson, E
MLA Citation
Clavien, P-A, Selzner, N, Morse, M, Selzner, M, and Paulson, E. "Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy." Surgery 131.4 (2002): 433-442.
PMID
11935134
Source
scival
Published In
Surgery
Volume
131
Issue
4
Publish Date
2002
Start Page
433
End Page
442
DOI
10.1067/msy.2002.122374

Editorial overview: Priming, boosting, measuring

Authors
Bunce, CJ; Morse, MA
MLA Citation
Bunce, CJ, and Morse, MA. "Editorial overview: Priming, boosting, measuring." Current Opinion in Molecular Therapeutics 4.1 (2002): 13-14.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
4
Issue
1
Publish Date
2002
Start Page
13
End Page
14

Technology evaluation: ISIS-2503, Isis Pharmaceuticals.

ISIS-2503, a 20-mer antisense oligonucleotide that inhibits Ha-Ras expression, is being developed by Isis Pharmaceuticals Inc as a potential treatmentfor cancer, particularly tumors that commonly have abnormalities of Ras function. It is in phase II trials. According to an April 2001 report by Bear Stearns & Co, Elan Corp plc had an unspecified collaboration with Isis for the development of ISIS-2503 [419357], but Isis later clarified that there was no agreement between the two companies and that ISIS-2503 had merely been used for the 'OraSense' joint venture that explores the use of antisense oligonucleotidesfor oral administration [419673].

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: ISIS-2503, Isis Pharmaceuticals." Curr Opin Mol Ther 3.6 (December 2001): 589-594.
PMID
11804274
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
6
Publish Date
2001
Start Page
589
End Page
594

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

BACKGROUND: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. METHODS: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT. RESULTS: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. CONCLUSIONS: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.

Authors
White, RR; Hurwitz, HI; Morse, MA; Lee, C; Anscher, MS; Paulson, EK; Gottfried, MR; Baillie, J; Branch, MS; Jowell, PS; McGrath, KM; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Hurwitz, HI, Morse, MA, Lee, C, Anscher, MS, Paulson, EK, Gottfried, MR, Baillie, J, Branch, MS, Jowell, PS, McGrath, KM, Clary, BM, Pappas, TN, and Tyler, DS. "Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas." Ann Surg Oncol 8.10 (December 2001): 758-765.
PMID
11776488
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
8
Issue
10
Publish Date
2001
Start Page
758
End Page
765

Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival.

BACKGROUND: Up to 30% of patients with locally advanced rectal cancer have a complete clinical or pathologic response to neoadjuvant chemoradiation. This study analyzes complete clinical and pathologic responders among a large group of rectal cancer patients treated with neoadjuvant chemoradiation. METHODS: From 1987 to 2000, 141 consecutive patients with biopsy-proven, locally advanced rectal cancer were treated with preoperative 5-fluorouracil-based chemotherapy and radiation. Clinical restaging after treatment consisted of proctoscopic examination and often computed tomography scan. One hundred forty patients then underwent operative resection, with results tracked in a database. Standard statistical methods were used to examine the outcomes of those patients with complete clinical or pathologic responses. RESULTS: No demographic differences were detected between either clinical complete and clinical partial responders or pathologic complete and pathologic partial responders. The positive predictive value of clinical restaging was 60%, and accuracy was 82%. By use of the Kaplan-Meier life table analysis, clinical complete responders had no advantage in local recurrence, disease-free survival, or overall survival rates when compared with clinical partial responders. Pathologic complete responders also had no recurrence or survival advantage when compared with pathologic partial responders. Of the 34 pathologic T0 tumors, 4 (13%) had lymph node metastases. CONCLUSIONS: Clinical assessment of complete response to neoadjuvant chemoradiation is unreliable. Micrometastatic disease persists in a proportion of patients despite pathologic complete response. Observation or local excision for patients thought to be complete responders should be undertaken with caution.

Authors
Onaitis, MW; Noone, RB; Fields, R; Hurwitz, H; Morse, M; Jowell, P; McGrath, K; Lee, C; Anscher, MS; Clary, B; Mantyh, C; Pappas, TN; Ludwig, K; Seigler, HF; Tyler, DS
MLA Citation
Onaitis, MW, Noone, RB, Fields, R, Hurwitz, H, Morse, M, Jowell, P, McGrath, K, Lee, C, Anscher, MS, Clary, B, Mantyh, C, Pappas, TN, Ludwig, K, Seigler, HF, and Tyler, DS. "Complete response to neoadjuvant chemoradiation for rectal cancer does not influence survival." Ann Surg Oncol 8.10 (December 2001): 801-806.
PMID
11776494
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
8
Issue
10
Publish Date
2001
Start Page
801
End Page
806

Quantitating antigen specific T cell responses in peripheral blood: A comparison of peptide MHC tetramer, ELISpot and intracellular cytokine analysis.

Authors
Hobeika, AC; Peplinski, S; Morse, MA; Mosca, PJ; Clay, TC; Lyerly, HK
MLA Citation
Hobeika, AC, Peplinski, S, Morse, MA, Mosca, PJ, Clay, TC, and Lyerly, HK. "Quantitating antigen specific T cell responses in peripheral blood: A comparison of peptide MHC tetramer, ELISpot and intracellular cytokine analysis." November 16, 2001.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
23A
End Page
23A

Enumerating functionally mature monocyte-derived dendritic cells for use in cancer immunotherapy.

Authors
Colling, KL; Hobeika, AC; Mosca, PJ; Clay, TM; Lyerly, HK; Morse, MA
MLA Citation
Colling, KL, Hobeika, AC, Mosca, PJ, Clay, TM, Lyerly, HK, and Morse, MA. "Enumerating functionally mature monocyte-derived dendritic cells for use in cancer immunotherapy." November 16, 2001.
Source
wos-lite
Published In
Blood
Volume
98
Issue
11
Publish Date
2001
Start Page
851A
End Page
851A

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Authors
White, RR; Paulson, EK; Freed, KS; Keogan, MT; Hurwitz, HI; Lee, C; Morse, MA; Gottfried, MR; Baillie, J; Branch, MS; Jowell, PS; McGrath, KM; Clary, BM; Pappas, TN; Tyler, DS
MLA Citation
White, RR, Paulson, EK, Freed, KS, Keogan, MT, Hurwitz, HI, Lee, C, Morse, MA, Gottfried, MR, Baillie, J, Branch, MS, Jowell, PS, McGrath, KM, Clary, BM, Pappas, TN, and Tyler, DS. "Staging of pancreatic cancer before and after neoadjuvant chemoradiation." J Gastrointest Surg 5.6 (November 2001): 626-633.
PMID
12086901
Source
pubmed
Published In
Journal of Gastrointestinal Surgery
Volume
5
Issue
6
Publish Date
2001
Start Page
626
End Page
633

The role of glutathione S-transferase P1-1 in colorectal cancer: friend or foe?

Authors
Morse, MA
MLA Citation
Morse, MA. "The role of glutathione S-transferase P1-1 in colorectal cancer: friend or foe?." Gastroenterology 121.4 (October 2001): 1010-1013.
PMID
11606516
Source
pubmed
Published In
Gastroenterology
Volume
121
Issue
4
Publish Date
2001
Start Page
1010
End Page
1013

Technology evaluation: CEA-TRICOM, Therion Biologics Corp.

Therion Biologics, the NCI and Aventis Pasteur are investigating CEA-TRICOM, a recombinant, pox virus-based vaccine that incorporates a triple dose of costimulatory molecules as well as the carcinoembryonic antigen (CEA) tumor antigen, for the potential treatment of colorectal cancer. CEA-TRICOM is designed to stimulate and strengthen the body's immune system to kill colorectal cancer cells. CEA-TRICOM is administered in a priming and boosting protocol using two unique pox virus vectors, rV-CEA-TRICOM (recombinant vaccinia vector) and rF-CEA-TRICOM (recombinant fowlpox vector). The TRICOM component of both rV-CEA-TRICOM and rF-CEA-TRICOM comprises three costimulatory molecule transgenes (B7-1, ICAM-1 and LFA-3) [414643], [414645], known to elicit strong cellular immune responses necessary for complete tumor destruction. In preclinical studies conducted by the NCI and Therion, researchers have demonstrated that this combination of three costimulatory molecules dramatically boosts the immune response to eradicate cancer in murine models [399610], [414631]. In February 2001, Therion Biologics and the NCI initiated a phase I trial of CEA-TRICOM [399610]. The phase I trial of CEA-TRICOM is designed to demonstrate proof-of-principle for using multiple costimulatory molecules in conjunction with a tumor antigen to improve the strength of cellular immune responses. It is a multistage, dose-escalation study that will assess the safety and immunologic effects of CEA-TRICOM in up to 42 patients who have advanced metastatic colorectal cancer. Subjects will receive rF-CEA-TRICOM alone, rV-CEA-TRICOM followed by booster vaccinations with rF-CEA-TRICOM or rV-CEA-TRICOM followed by rF-CEA-TRICOM and GM-CSF adjuvant. The primary measure of immune response will be the level of CEA-specific T-cells stimulated by vaccination, with levels of CEA-expressing tumor cells in the blood used as a potential secondary measure of treatment effect [399610].

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: CEA-TRICOM, Therion Biologics Corp." Curr Opin Mol Ther 3.4 (August 2001): 407-412.
PMID
11525565
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
4
Publish Date
2001
Start Page
407
End Page
412

American Society of Clinical Oncology - 37th Annual Meeting. Novel antitumor agents. 12-15 May 2001, San Francisco, CA, USA.

Authors
Morse, MA
MLA Citation
Morse, MA. "American Society of Clinical Oncology - 37th Annual Meeting. Novel antitumor agents. 12-15 May 2001, San Francisco, CA, USA." IDrugs 4.8 (August 2001): 853-856.
PMID
15973572
Source
pubmed
Published In
Idrugs
Volume
4
Issue
8
Publish Date
2001
Start Page
853
End Page
856

American Society of Clinical Oncology - 37th Annual Meeting. Small molecule tyrosine kinase inhibitors. 12-15 May 2001, San Francisco, CA, USA.

Authors
Morse, MA
MLA Citation
Morse, MA. "American Society of Clinical Oncology - 37th Annual Meeting. Small molecule tyrosine kinase inhibitors. 12-15 May 2001, San Francisco, CA, USA." IDrugs 4.8 (August 2001): 857-859.
PMID
15973573
Source
pubmed
Published In
Idrugs
Volume
4
Issue
8
Publish Date
2001
Start Page
857
End Page
859

Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates.

Laboratory isolates of human immunodeficiency virus type 1 (HIV-1) that utilize CXCR4 as a coreceptor infect primary human macrophages inefficiently even though these express a low but detectable level of cell surface CXCR4. In contrast, infection of primary macrophages by primary CXCR4-tropic HIV-1 isolates is readily detectable. Here, we provide evidence suggesting that this difference in cell tropism results from a higher requirement for cell surface CXCR4 for infection by laboratory HIV-1 isolates. Transfected COS7 cells that express a high level of CD4 but a low level of CXCR4 were infected significantly more efficiently by two primary CXCR4-tropic HIV-1 isolates compared to the prototypic laboratory HIV-1 isolate IIIB. More importantly, overexpression of either wild-type or signaling-defective CXCR4 on primary macrophages dramatically enhanced the efficiency of infection by the laboratory HIV-1 isolate yet only modestly enhanced infection by either primary CXCR4-tropic virus. Overexpression of CD4 had, in contrast, only a limited effect on macrophage infection by the laboratory HIV-1, although infection by the primary isolates was markedly enhanced. We therefore conclude that the laboratory CXCR4-tropic HIV-1 isolate exhibits a significantly higher CXCR4 requirement for efficient infection than do the primary CXCR4-tropic isolates and that this difference can explain the poor ability of the laboratory HIV-1 isolate to replicate in primary macrophages. More generally, we propose that the cell tropisms displayed by different strains of HIV-1 in culture can largely be explained on the basis of differential requirements for cell surface CD4 and/or coreceptor expression levels.

Authors
Tokunaga, K; Greenberg, ML; Morse, MA; Cumming, RI; Lyerly, HK; Cullen, BR
MLA Citation
Tokunaga, K, Greenberg, ML, Morse, MA, Cumming, RI, Lyerly, HK, and Cullen, BR. "Molecular basis for cell tropism of CXCR4-dependent human immunodeficiency virus type 1 isolates." J Virol 75.15 (August 2001): 6776-6785.
PMID
11435556
Source
pubmed
Published In
Journal of virology
Volume
75
Issue
15
Publish Date
2001
Start Page
6776
End Page
6785
DOI
10.1128/JVI.75.15.6776-6785.2001

Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat.

BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) and N-(4-hydroxyphenyl)retinamide (4-HPR) are effective chemopreventive agents against epithelial tumors in the oral cavity, breast, and prostate. We tested the inhibitory activity of these retinoids against N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus. METHODS: Male Fischer 344 rats were randomly assigned to receive diets either lacking or containing 9-cis-RA or 4-HPR for 1 week before tumor initiation with NMBA and then for the duration of the study. NMBA metabolism, O(6)-methylguanine adduct formation, and cytochrome P450 messenger RNA (mRNA) expression in the esophagi of the rats were studied to investigate the mechanisms by which dietary 4-HPR affects tumorigenesis. All statistical tests were two-sided. RESULTS: Dietary 4-HPR resulted in a dose-dependent and statistically significant enhancement (P<.05) of tumorigenesis in response to NMBA. In two different tumor bioassays, the mean tumor multiplicity for rats fed the highest concentration of dietary 4-HPR (0.8 g/kg diet) was increased by 5.9 tumors (95% confidence interval [CI] = 1.7 to 10.1 tumors) and 6.7 tumors (95% CI = 5.6 to 7.8 tumors) compared with the mean tumor multiplicity for rats that received the control diet lacking 4-HPR. Animals fed diets containing 9-cis-RA displayed no statistically significant increase in tumorigenesis. Compared with animals fed a diet lacking 4-HPR, animals fed 4-HPR had increased NMBA metabolism in esophageal explant cultures and had higher levels of O(6)-methylguanine DNA adducts and CYP2A3 mRNA in their esophagi. CONCLUSIONS: Dietary 4-HPR enhances tumorigenesis in response to NMBA in the rat esophagus by increasing tumor initiation events. Dietary 4-HPR may exert paradoxical effects at some sites, such as the aerodigestive tract, by modulating the bioactivation of carcinogens in target tissues.

Authors
Gupta, A; Nines, R; Rodrigo, KA; Aziz, RA; Carlton, PS; Gray, DL; Steele, VE; Morse, MA; Stoner, GD
MLA Citation
Gupta, A, Nines, R, Rodrigo, KA, Aziz, RA, Carlton, PS, Gray, DL, Steele, VE, Morse, MA, and Stoner, GD. "Effects of dietary N-(4-hydroxyphenyl)retinamide on N-nitrosomethylbenzylamine metabolism and esophageal tumorigenesis in the Fischer 344 rat." J Natl Cancer Inst 93.13 (July 4, 2001): 990-998.
PMID
11438564
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
93
Issue
13
Publish Date
2001
Start Page
990
End Page
998

Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience.

OBJECTIVE: To examine clinical outcomes in patients receiving neoadjuvant chemoradiation for locally advanced rectal adenocarcinoma. SUMMARY BACKGROUND DATA: Preoperative radiation therapy, either alone or in combination with 5-fluorouracil-based chemotherapy, has proven both safe and effective in the treatment of rectal cancer. However, data are lacking regarding which subgroups of patients benefit from the therapy in terms of decreased local recurrence and increased survival rates. METHODS: A retrospective chart review was performed on 141 consecutive patients who received neoadjuvant chemoradiation (5-fluorouracil +/- cisplatin and 4,500-5,040 cGy) for biopsy-proven locally advanced adenocarcinoma of the rectum. Surgery was performed 4 to 8 weeks after completion of chemoradiation. Standard statistical methods were used to analyze recurrence and survival. RESULTS: Median follow-up was 27 months, and mean age was 59 years (range 28-81). Mean tumor distance from the anal verge was 6 cm (range 1-15). Of those staged before surgery with endorectal ultrasound or magnetic resonance imaging, 57% of stage II patients and 82% of stage III patients were downstaged. The chemotherapeutic regimens were well tolerated, and resections were performed on 140 patients. The percentage of sphincter-sparing procedures increased from 20% before 1996 to 76% after 1996. On pathologic analysis, 24% of specimens were T0. However, postoperative pathologic T stage had no effect on either recurrence or survival. Positive lymph node status predicted increased local recurrence and decreased survival. CONCLUSIONS: Neoadjuvant chemoradiation is safe, effective, and well tolerated. Postoperative lymph node status is the only independent predictor of recurrence and survival.

Authors
Onaitis, MW; Noone, RB; Hartwig, M; Hurwitz, H; Morse, M; Jowell, P; McGrath, K; Lee, C; Anscher, MS; Clary, B; Mantyh, C; Pappas, TN; Ludwig, K; Seigler, HF; Tyler, DS
MLA Citation
Onaitis, MW, Noone, RB, Hartwig, M, Hurwitz, H, Morse, M, Jowell, P, McGrath, K, Lee, C, Anscher, MS, Clary, B, Mantyh, C, Pappas, TN, Ludwig, K, Seigler, HF, and Tyler, DS. "Neoadjuvant chemoradiation for rectal cancer: analysis of clinical outcomes from a 13-year institutional experience." Ann Surg 233.6 (June 2001): 778-785.
PMID
11371736
Source
pubmed
Published In
Annals of Surgery
Volume
233
Issue
6
Publish Date
2001
Start Page
778
End Page
785

Effects of 10-hydroxycamptothecin, delivered from locally injectable poly(lactide-co-glycolide) microspheres, in a murine human oral squamous cell carcinoma regression model.

This study investigated whether local delivery of 10-hydroxycamptothecin provides effective inductive chemotherapy as assessed by significant tumor reduction. Established tumorigenic human oral squamous cell carcinoma cells were used for these experiments. The experimental groups were comprised of: control (blank (no drug) poly(lactide-co-glycolide) (PLGA) microspheres), intraperitoneal 10-hydroxycamptothecin delivery + blank microspheres, local bolus 10-hydroxycamptothecin + blank microspheres, and PLGA controlled-release microspheres. The 10-hydroxycamptothecin dose administered was 12 mg/kg (bolus-intraperitoneal, local) or controlled-release over 10 days. Regardless of delivery route, 10-hydroxycamptothecin significantly reduces tumor volume. However, PLGA microspheres provide significantly higher intratumor-drug concentrations (approximately 10 and 100 fold higher) relative to local bolus and intraperitoneal routes, respectively. Also, only the PLGA microspheres significantly reduced tumor weights. Camptothecin clinical applications are limited by drug inactivation at physiological pH and the need for sustained infusions. However, due to their acidic, camptothecin-stabilizing microclimate, PLGA microspheres could provide a novel delivery system for camptothecin-based induction chemotherapy.

Authors
Mallery, SR; Shenderova, A; Pei, P; Begum, S; Ciminieri, JR; Wilson, RF; Casto, BC; Schuller, DE; Morse, MA
MLA Citation
Mallery, SR, Shenderova, A, Pei, P, Begum, S, Ciminieri, JR, Wilson, RF, Casto, BC, Schuller, DE, and Morse, MA. "Effects of 10-hydroxycamptothecin, delivered from locally injectable poly(lactide-co-glycolide) microspheres, in a murine human oral squamous cell carcinoma regression model." Anticancer Res 21.3B (May 2001): 1713-1722.
PMID
11497251
Source
pubmed
Published In
Anticancer research
Volume
21
Issue
3B
Publish Date
2001
Start Page
1713
End Page
1722

Assays for monitoring cellular immune responses to active immunotherapy of cancer.

Numerous cancer immunotherapy strategies are currently being tested in clinical trials. Although clinical efficacy will be the final test of these approaches, the long and complicated developmental pathway for these agents necessitates evaluating immunological responses as intermediate markers of the most likely candidates for success. This has emphasized the need for assays that accurately detect and quantitate T cell-mediated, antigen-specific immune responses. This review evaluates the currently used in vivo and in vitro methods of assessing T-cell number and function, including delayed-type hypersensitivity, tetramer analysis, ELISPOT, flow cytometry-based analysis of cytokine expression, and PCR-based detection of T-cell receptor gene usage or cytokine production. We provide examples of how each has been used to monitor recent clinical trials and a discussion of how well each correlates with clinical outcome.

Authors
Clay, TM; Hobeika, AC; Mosca, PJ; Lyerly, HK; Morse, MA
MLA Citation
Clay, TM, Hobeika, AC, Mosca, PJ, Lyerly, HK, and Morse, MA. "Assays for monitoring cellular immune responses to active immunotherapy of cancer." Clin Cancer Res 7.5 (May 2001): 1127-1135. (Review)
PMID
11350875
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
7
Issue
5
Publish Date
2001
Start Page
1127
End Page
1135

Surrogate markers of effective anti-tumor immunity.

Authors
Lyerly, HK; Morse, MA; Clay, TM
MLA Citation
Lyerly, HK, Morse, MA, and Clay, TM. "Surrogate markers of effective anti-tumor immunity." Ann Surg Oncol 8.3 (April 2001): 190-191.
PMID
11314932
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
8
Issue
3
Publish Date
2001
Start Page
190
End Page
191

Monitoring and ensuring safety during clinical research.

Increased numbers of clinical trials, many of which are large, multicenter, and sometimes international, and the marked shift of funding for clinical trials to industry have made apparent the inadequacy of mechanisms for protecting human subjects that were developed when clinical research was generally carried out on a small scale at single institutions. To address concerns regarding the protection of human subjects, a group of professionals with expertise in various aspects of clinical trials was assembled in May 2000. Participants described and evaluated the mechanisms by which clinical trials are monitored, focusing on adverse event reporting and the processes by which various parties with oversight responsibilities interact in the course of these trials. In this article, we describe the manner in which adverse event reporting might function to enhance safety and the role of data monitoring committees in using aggregate data from these reports, outline the problems that now exist for institutional review boards as they are faced with multiple adverse event reports from clinical trials while conducting continuing review, and offer recommendations for improving the current approach.

Authors
Morse, MA; Califf, RM; Sugarman, J
MLA Citation
Morse, MA, Califf, RM, and Sugarman, J. "Monitoring and ensuring safety during clinical research." JAMA 285.9 (March 7, 2001): 1201-1205.
PMID
11231751
Source
pubmed
Published In
JAMA : the journal of the American Medical Association
Volume
285
Issue
9
Publish Date
2001
Start Page
1201
End Page
1205

Surrogate markers of response to cancer immunotherapy.

Clinically effective cancer immunotherapy has been sought for more than 100 years and has been recently applied most successfully in strategies that passively deliver immune effectors such as monoclonal antibodies (anti-CD20 for lymphoma and anti-HER2/neu for breast cancer), donor lymphocyte infusions in chronic myelongenous leukemia and non-myeloablative allogeneic peripheral blood progenitor transplants for renal cell carcinoma. There is mounting enthusiasm for strategies employing active stimulation of antitumour immune responses. These include vaccines based on tumour antigen proteins and peptides, autologous, allogeneic or gene-modified tumour cells, dendritic cells and antigen-encoding viral vector constructs. Indeed, randomised Phase III clinical trials of autologous tumour cell vaccines for colorectal cancer demonstrated an improvement in disease free survival and a trend toward improved overall survival [1]. Despite these preliminary successes, it is clear that the many strategies under development cannot all be evaluated for survival benefit in large clinical trials that require many years, patients and resources to complete. This highlights the need to develop intermediate markers to help prioritise which agents to test in prospective randomised Phase III trials.

Authors
Morse, MA; Clay, TM; Hobeika, AC; Mosca, PJ; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Hobeika, AC, Mosca, PJ, and Lyerly, HK. "Surrogate markers of response to cancer immunotherapy." Expert Opin Biol Ther 1.2 (March 2001): 153-158.
PMID
11727526
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
1
Issue
2
Publish Date
2001
Start Page
153
End Page
158
DOI
10.1517/14712598.1.2.153

Direct detection of cellular immune responses to cancer vaccines.

The evaluation of cancer immunotherapy is predicated on the hypothesis that markers of tumor antigen-specific T-cell immunity will cone-late with clinical efficacy. Establishing which candidate vaccines should enter large-scale clinical trials will necessitate optimal application of immunologic monitoring assays. Evidence suggests that available techniques are adequate for the direct detection of clinically significant antigen-specific T-cell responses from tissue specimens. To achieve this goal, it is important to have an understanding of individual methods and their limitations, to include appropriate control antigens in the monitoring strategy, and to incorporate statistical considerations into the design and analysis of such studies.

Authors
Mosca, PJ; Hobeika, AC; Clay, TM; Morse, MA; Lyerly, HK
MLA Citation
Mosca, PJ, Hobeika, AC, Clay, TM, Morse, MA, and Lyerly, HK. "Direct detection of cellular immune responses to cancer vaccines." Surgery 129.3 (March 2001): 248-254. (Review)
PMID
11231452
Source
pubmed
Published In
Surgery
Volume
129
Issue
3
Publish Date
2001
Start Page
248
End Page
254
DOI
10.1067/msy.2001.108609

Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.

Dysfunction in the physiological pathways of programmed cell death may promote proliferation of malignant cells, and correction of such defects may selectively induce apoptosis in cancer cells. We measured the levels of ceramide, a candidate lipid mediator of apoptosis, in human metastatic colorectal cancer and tested in vitro and in vivo effects of various ceramide analogues in inducing apoptosis in metastatic colon cancer. Human colon cancer showed a > 50% decrease in the cellular content of ceramide when compared with normal colon mucosa. Application of ceramide analogues and ceramidase inhibitors induced rapid cell death through activation of various proapoptotic molecules, such as caspases and release of cytochrome c. Ceramidase inhibition increases the ceramide content of tumor cells, resulting in maximum activation of the apoptotic cascade. Normal liver cells were completely resistant to inhibitors of ceramidases. Treatment of nude mice with B13, the most potent ceramidase inhibitor, completely prevented tumor growth using two different aggressive human colon cancer cell lines metastatic to the liver. Therefore, B13 and related analogues of ceramide and inhibitors of ceramidases offer a promising therapeutic strategy with selective toxicity toward malignant but not normal cells. These studies also suggest that the ceramide content in cancer cells might be involved in the pathogenesis of tumor growth in vitro and in vivo.

Authors
Selzner, M; Bielawska, A; Morse, MA; Rüdiger, HA; Sindram, D; Hannun, YA; Clavien, PA
MLA Citation
Selzner, M, Bielawska, A, Morse, MA, Rüdiger, HA, Sindram, D, Hannun, YA, and Clavien, PA. "Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer." Cancer Res 61.3 (February 1, 2001): 1233-1240.
PMID
11221856
Source
pubmed
Published In
Cancer Research
Volume
61
Issue
3
Publish Date
2001
Start Page
1233
End Page
1240

Technology evaluation: BLP-25, Biomira Inc.

Biomira is developing the MUC-1 peptide-based vaccine BLP-25 for the potential treatment of cancer. It is in phase II trials for non-small cell lung cancer (NSCLC) [335997], [353448], [384703]. The MUC-1 mucin secreted by cancer cells has been shown to decrease the activity of certain immune response cells, including killer T-cells, and can inhibit the immune T-cell response by > 70%. BLP-25 is designed to target an immune response to the MUC-1 mucin that is shown by > 90% of common solid tumors. The introduction of IL-2 reverses the T-cell suppression caused by MUC-1 mucin, and enhances the cellular immune response > 100-fold. Biomira has been incorporating IL-2 into a liposomal delivery system for BLP-25 [274576]. In late 1998, Biomira entered into a research collaboration with Axis Genetics. The collaboration will assess the further potential of therapeutic cancer vaccines against MUC-1. Each company has developed a vaccine targeting the MUC-1 peptide and Biomira will be evaluating Axis's vaccine in preclinical trials [313395]. In December 1996, Biomira signed a licensing agreement whereby it was granted the rights to use Dana-Farber Cancer Institute's two US patents relating to MUC-1 (based on pioneering work at the Institute on the identification of cell-surface molecules that are characteristic of cancer cells) for peptide-based cancer vaccines [228101].

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: BLP-25, Biomira Inc." Curr Opin Mol Ther 3.1 (February 2001): 102-105. (Review)
PMID
11249725
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
1
Publish Date
2001
Start Page
102
End Page
105

Technology evaluation: VEGF165 gene therapy, Valentis Inc.

Valentis Inc, formerly GeneMedicine, is developing a vascular endothelial growth factor (VEGF165) non-viral gene therapy using its proprietary PINC polymer for plasmid condensation. Two physician-initiated phase II angioplasty trials are ongoing, one for treating peripheral vascular disease and one for treating coronary artery disease [281714], [347153]. In February 2000, the trials were expected to be completed in the fourth quarter of 2000 [356225]; however, in October 2000, it was reported that the trial for peripheral vascular disease would be completed in the first quarter of 2001 [385232]. In March 2000, Valentis initiated a trial incorporating Valentis's DOTMA-based cationic lipid gene delivery system and the VEGF165 gene with Eurogene's local collar-reservoir delivery device. The trial is designed to demonstrate that the VEGF165 gene, delivered locally to the outside surface of a blood vessel, will transfect and express in the smooth muscle cells of the vessel wall [360683]. In March 1999, Valentis was awarded with a Phase II SBIR grant of $686,260. The aim of grant was to advance the development of non-viral gene therapies for ischemia. Specifically, Valentis intended to select an optimal promoter to be used with the VEGF expression plasmid. Valentis also intended to evaluate the gene therapy system in a rabbit ischemia model and complete the necessary preclinical studies for submission of an IND [318137].

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: VEGF165 gene therapy, Valentis Inc." Curr Opin Mol Ther 3.1 (February 2001): 97-101. (Review)
PMID
11249737
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
1
Publish Date
2001
Start Page
97
End Page
101

Monitoring cellular immune responses to cancer immunotherapy.

Many clinical trials are testing the feasibility of stimulating the immune system to treat cancer. Although the efficacy of this approach will ultimately be determined by clinically relevant endpoints, detection of the magnitude and activity of the immune response is an important intermediate point in the development of these strategies. Assays that predict clinically relevant endpoints are particularly desirable for helping to determine which strategies should ultimately be tested in larger randomized clinical trials. In this review, we will discuss these cellular immunological assays and the current status of their role in clinical trials of immunotherapy.

Authors
Morse, MA; Clay, TM; Hobeika, AC; Mosca, PJ; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, Hobeika, AC, Mosca, PJ, and Lyerly, HK. "Monitoring cellular immune responses to cancer immunotherapy." Curr Opin Mol Ther 3.1 (February 2001): 45-52. (Review)
PMID
11249731
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
1
Publish Date
2001
Start Page
45
End Page
52

Editorial overview - A cornucopia of strategies for the immunotherapy of cancer

Authors
Morse, MA; Bunce, C
MLA Citation
Morse, MA, and Bunce, C. "Editorial overview - A cornucopia of strategies for the immunotherapy of cancer." CURRENT OPINION IN MOLECULAR THERAPEUTICS 3.1 (February 2001): 13-14.
Source
wos-lite
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
1
Publish Date
2001
Start Page
13
End Page
14

Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate.

Previous studies in our laboratory have shown that 6-phenylhexyl isothiocyanate (PHITC), enhances N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats while the shorter chain analogs, phenylethyl isothiocyanate (PEITC), and 3-phenylpropyl isothiocyanate (PPITC), inhibit NMBA-induced esophageal tumorigenesis. To test the hypothesis that PHITC influences the promotional stage of esophageal tumorigenesis, groups of 22-27 rats were dosed with vehicle or NMBA three times a week for 5 week, and fed a modified AIN-76A diet containing PHITC at concentrations of 0.0, 1.0, and 2.5 micromol/g. At the 25th week, the rats were killed, esophagi harvested and tumors counted. In the groups that received NMBA+PHITC, apparent but statistically insignificant increases in tumor multiplicity of 32 and 42% were found in comparison to rats treated with NMBA alone. A higher frequency of dysplastic lesions was found in rats treated with NMBA+2.5 micromol/g PHITC (71%) when compared to rats treated with NMBA only (12%). To test whether PHITC increased cellular proliferation, we evaluated proliferating cell nuclear antigen (PCNA) expression by immunohistochemistry. While there were no significant increases in PCNA staining in rats treated with NMBA+PHITC compared to rats treated with NMBA only, rats treated with PHITC only had a significantly higher PCNA index compared to untreated controls. Expression of cyclin D1, another biomarker of proliferation, was analyzed by semi-quantitative reverse transcription-polymerase chain reaction. There were no significant increases in cyclin D1 expression in groups treated with NMBA+PHITC compared to the group treated with NMBA only. Thus, while the data suggest a promotional effect by PHITC as manifested by a significant increase in dysplastic leukoplakia by the high dose of PHITC and an increase in the PCNA index by PHITC alone, PHITC does not appear to have a significant effect on esophageal cell proliferation.

Authors
Hudson, TS; Carlton, PS; Gupta, A; Stoner, GD; Morse, MA
MLA Citation
Hudson, TS, Carlton, PS, Gupta, A, Stoner, GD, and Morse, MA. "Investigation of the enhancement of N-nitrosomethylbenzylamine-induced esophageal tumorigenesis by 6-phenylhexyl isothiocyanate." Cancer Lett 162.1 (January 10, 2001): 19-26.
PMID
11121858
Source
pubmed
Published In
Cancer Letters
Volume
162
Issue
1
Publish Date
2001
Start Page
19
End Page
26

Quantitating therapeutically relevant T-cell responses to cancer vaccines.

Successful application of active immunotherapy to the treatment of cancer will require stimulation of potent antigen-specific T-cell responses. It is not known how numerous or how potent these T cells must be in order to abrogate tumors, but the levels of immunity needed to control chronic viral infections may provide estimates for comparison. Evaluation of the efficacy of a vaccine strategy in attaining these levels of immunity will depend on the use of assays that create a picture of T-cell number and function that correlates with clinical outcomes. We discuss the currently available in vivo and in vitro T-cell assays and their relevance for detecting therapeutic levels of T-cell activity. We also propose a strategy for efficiently evaluating the immunologic efficacy of cancer vaccines so that the most promising candidates can be brought more rapidly into definitive clinical trials.

Authors
Hobeika, AC; Clay, TM; Mosca, PJ; Lyerly, HK; Morse, MA
MLA Citation
Hobeika, AC, Clay, TM, Mosca, PJ, Lyerly, HK, and Morse, MA. "Quantitating therapeutically relevant T-cell responses to cancer vaccines." Crit Rev Immunol 21.1-3 (2001): 287-297. (Review)
PMID
11642610
Source
pubmed
Published In
Critical Reviews in Immunology
Volume
21
Issue
1-3
Publish Date
2001
Start Page
287
End Page
297

The role of local institutional review boards in protecting human research subjects [3]

Authors
Burman, WJ; Schooley, RT; Morse, MA; Califf, RM; Sugarman, J
MLA Citation
Burman, WJ, Schooley, RT, Morse, MA, Califf, RM, and Sugarman, J. "The role of local institutional review boards in protecting human research subjects [3]." Journal of the American Medical Association 285.21 (2001): 2713--.
PMID
11386919
Source
scival
Published In
Journal of the American Medical Association
Volume
285
Issue
21
Publish Date
2001
Start Page
2713-

A cornucopia of strategies for the immunotherapy of cancer

Authors
Morse, MA; Bunce, C
MLA Citation
Morse, MA, and Bunce, C. "A cornucopia of strategies for the immunotherapy of cancer." Current Opinion in Molecular Therapeutics 3.1 (2001): 13-14.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
3
Issue
1
Publish Date
2001
Start Page
13
End Page
14

Effects of 10-hydroxycamptothecin, delivered from locally injectable poly(lactide-co-glycolide) microspheres, in a murine human oral squamous cell carcinoma regression model

This study investigated whether local delivery of 10-hydroxycamptothecin provides effective inductive chemotherapy as assessed by significant tumor reduction. Established tumorigenic human oral squamous cell carcinoma cells were used for these experiments. The experimental groups were comprised of: control (blank (no drug) poly(lactide-co-glycolide) (PLGA) microspheres), intraperitoneal 10-hydroxycamptothecin delivery + blank microspheres, local bolus 10-hydroxycamptothecin + blank microspheres, and PLGA controlled-release microspheres. The 10-hydroxycamptothecin dose administered was 12 mg/kg (bolus-intraperitoneal, local) or controlled-release over 10 days. Regardless of delivery route, 10-hydroxycamptothecin significantly reduces tumor volume. However, PLGA microspheres provide significantly higher intratumor-drug concentrations (∼10 and 100 fold higher) relative to local bolus and intraperitoneal routes, respectively. Also, only the PLGA microspheres significantly reduced tumor weights. Camptothecin clinical applications are limited by drug inactivation at physiological pH and the need for sustained infusions. However, due to their acidic, camptothecin- stabilizing microclimate, PLGA microspheres could provide a novel delivery system for camptothecin-based induction chemotherapy.

Authors
Mallery, SR; Shenderova, A; Pei, P; Begum, S; Ciminieri, JR; Wilson, RF; Casto, BC; Schuller, DE; Morse, MA
MLA Citation
Mallery, SR, Shenderova, A, Pei, P, Begum, S, Ciminieri, JR, Wilson, RF, Casto, BC, Schuller, DE, and Morse, MA. "Effects of 10-hydroxycamptothecin, delivered from locally injectable poly(lactide-co-glycolide) microspheres, in a murine human oral squamous cell carcinoma regression model." Anticancer Research 21.3 B (2001): 1713-1722.
Source
scival
Published In
Anticancer Research
Volume
21
Issue
3 B
Publish Date
2001
Start Page
1713
End Page
1722

Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer.

PURPOSE: To evaluate preoperative dendritic cell (DC) mobilization and tumor infiltration after administration of Flt3 ligand (Flt3L) to patients with metastatic colon cancer. PATIENTS AND METHODS: Twelve patients with colon cancer metastatic to the liver or lung received Flt3L (20 microg/kg/d subcutaneously for 14 days for one to three cycles at monthly intervals) before attempted metastasectomy. The number and phenotype of DCs mobilized into peripheral-blood mononuclear cells (PBMCs) were evaluated by flow cytometry. After surgical resection, metastatic tumor tissue was evaluated for DC infiltration. In vivo immune responses to recall antigens were measured. RESULTS: After Flt3L administration, on average, the total number of leukocytes in the peripheral blood increased from 5.9 +/- 1.0 x 10(3)/mm(3) to 11.2 +/- 3.8 x 10(3)/mm(3) (mean +/- SD, P: =. 0001). The percentage of CD11c(+)CD14(-) DCs in PBMCs increased from 2.4% +/- 1.8% to 8.8% +/- 4.7% (P: =.004). Delayed-type hypersensitivity (DTH) responses to recall antigens (CANDIDA:, mumps, and tetanus) showed marginally significant increases in reactivity after Flt3L administration (P: =.06, P: =.03, and P: =.08, respectively). An increase in the number of DCs was observed at the periphery of the tumors of patients who received Flt3L compared with those of patients who had not. CONCLUSION: Flt3L is capable of mobilizing DCs into the peripheral blood of patients with metastatic colon cancer and may be associated with increases in DC infiltration in the peritumoral regions. Flt3L mobilization is associated with a trend toward increased DTH responses to recall antigens in vivo. The use of Flt3L to increase circulating DCs for cancer immunotherapy should be considered.

Authors
Morse, MA; Nair, S; Fernandez-Casal, M; Deng, Y; St Peter, M; Williams, R; Hobeika, A; Mosca, P; Clay, T; Cumming, RI; Fisher, E; Clavien, P; Proia, AD; Niedzwiecki, D; Caron, D; Lyerly, HK
MLA Citation
Morse, MA, Nair, S, Fernandez-Casal, M, Deng, Y, St Peter, M, Williams, R, Hobeika, A, Mosca, P, Clay, T, Cumming, RI, Fisher, E, Clavien, P, Proia, AD, Niedzwiecki, D, Caron, D, and Lyerly, HK. "Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer." J Clin Oncol 18.23 (December 1, 2000): 3883-3893.
PMID
11099317
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
23
Publish Date
2000
Start Page
3883
End Page
3893
DOI
10.1200/JCO.2000.18.23.3883

Dendritic cell (DC) reconstitution after non-myeloablative allogeneic stem cell transplants.

Authors
Morse, MA; Rizzieri, D; Hobeika, AC; Chao, N; Lyerly, HK
MLA Citation
Morse, MA, Rizzieri, D, Hobeika, AC, Chao, N, and Lyerly, HK. "Dendritic cell (DC) reconstitution after non-myeloablative allogeneic stem cell transplants." November 16, 2000.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
305B
End Page
305B

Multiple signals are required for IL-12 production by Flt-3 ligand mobilized dendritic cells.

Authors
Mosca, PJ; Hobeika, AC; Clay, TM; Nair, SK; Thomas, EK; Caron, DA; Lyerly, HK; Morse, MA
MLA Citation
Mosca, PJ, Hobeika, AC, Clay, TM, Nair, SK, Thomas, EK, Caron, DA, Lyerly, HK, and Morse, MA. "Multiple signals are required for IL-12 production by Flt-3 ligand mobilized dendritic cells." November 16, 2000.
Source
wos-lite
Published In
Blood
Volume
96
Issue
11
Publish Date
2000
Start Page
295A
End Page
295A

A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment.

Dendritic cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal antigen presentation and T-cell activation. High cell surface expression of CD83 is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83 expression on DCs. We hypothesized that interleukin 12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating antigen-specific T cells. We used combinations of signaling through CD40, using CD40 ligand trimer (CD40L), and interferon gamma to demonstrate that CD83 expression is necessary but not sufficient for optimal production of IL-12 by DCs. Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals. By intracellular cytokine detection, we determined that only a subset of cells that express high levels of CD80 and CD83 generate large amounts of IL-12. DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T cell in vitro. These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.

Authors
Mosca, PJ; Hobeika, AC; Clay, TM; Nair, SK; Thomas, EK; Morse, MA; Lyerly, HK
MLA Citation
Mosca, PJ, Hobeika, AC, Clay, TM, Nair, SK, Thomas, EK, Morse, MA, and Lyerly, HK. "A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment." Blood 96.10 (November 15, 2000): 3499-3504.
PMID
11071647
Source
pubmed
Published In
Blood
Volume
96
Issue
10
Publish Date
2000
Start Page
3499
End Page
3504

Optimizing dendritic cell function by genetic modification.

Authors
Lyerly, HK; Clay, T; Morse, MA
MLA Citation
Lyerly, HK, Clay, T, and Morse, MA. "Optimizing dendritic cell function by genetic modification." J Natl Cancer Inst 92.15 (August 2, 2000): 1198-1199.
PMID
10922398
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
92
Issue
15
Publish Date
2000
Start Page
1198
End Page
1199

Technology evaluation: gene therapy (IL-2), Valentis Inc.

Cationic lipid-DNA complexes are being evaluated for local or systemic therapeutic gene transfer. These positively charged liposomes fuse with negatively charged cell membranes and deliver the enclosed plasmid and its encoded gene to target tissues. This system has relevance for delivering genes to both normal and damaged or malignant tissues including phagocytes, tumor cells, endothelium and possibly parenchymal cells. Among the approaches being actively evaluated is the delivery of immunostimulatory cytokine genes (such as IL-2, IFN alpha or IL-12) into tumors. It is hypothesized that the local cytokine release will attract or induce antitumor immune responses. Valentis, (formerly GeneMedicine), has developed a plasmid encoding human IL-2 complexed with the liposomal preparation of DOTMA and cholesterol and has initiated phase I studies of intratumoral injection in head and neck cancer patients. Other routes of administration (intravenous and intratracheal), cytokines (IL-2) and proprietary liposomal-DNA complexes are being evaluated in preclinical models.

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: gene therapy (IL-2), Valentis Inc." Curr Opin Mol Ther 2.4 (August 2000): 448-452. (Review)
PMID
11249776
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
2
Issue
4
Publish Date
2000
Start Page
448
End Page
452

Technology evaluation: Theratope, Biomira Inc.

Active specific immunotherapy, the use of 'vaccines' to stimulate therapeutic tumor antigen-specific immune responses, holds promise as a complementary approach to chemotherapy, radiation and surgery for the treatment of patients with cancers that have a high risk of relapse or progressive disease. Important components of an agent used for active immunotherapy are immunogens in the form of tumor-associated antigen(s) and an adjuvant or carrier molecule to promote presentation of the antigen to the immune effector cells. Possible antigens include tumor-expressed proteins or carbohydrate structures such as the glycoprotein mucin and its epitopes. The Theratope vaccine, consisting of a synthetic mimic of the mucin-associated glycan epitope STn conjugated to the carrier molecule keyhole limpet hemocyanin, has been developed for immunizing patients with mucin-expressing tumors. In murine and human studies, the vaccine has been shown to stimulate anti-STn antibodies and mucin-specific T-cell responses. The immune response is augmented by pretreatment with intravenous cyclophosphamide that serves to inhibit suppressor T-cells. Phase II studies suggested a survival benefit for breast cancer patients who received the Theratope vaccine after intravenous cyclophosphamide. A multinational phase III study testing the Theratope vaccine in patients with metastatic breast cancer who have had a clinical response or stability of disease is ongoing. Other malignancies for which the vaccine may be applicable include ovarian and gastrointestinal cancers.

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: Theratope, Biomira Inc." Curr Opin Mol Ther 2.4 (August 2000): 453-458. (Review)
PMID
11249777
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
2
Issue
4
Publish Date
2000
Start Page
453
End Page
458

American Society of Clinical Oncology - 36th Annual Meeting.

The American Society of Clinical Oncology (ASCO) 36th Annual Meeting, which took place from 20-23 May 2000 in New Orleans, was, as usual, a large, well-attended, internationally-represented meeting of cancer specialists. Both clinical trials of well established drugs for the treatment of cancer, as well as novel agents under development were presented in poster sessions, poster discussion sessions and large oral sessions. The prominent areas of new drug development presented were anti-angiogenic agents, tyrosine kinase inhibitors, immunotherapeutics and agents that modify the pharmacology or pharmacodynamics of chemotherapeutic agents. Sessions highlighting the translational development of several compounds with other mechanisms of action were also well attended. While there were no agents with unexpectedly dramatic clinical benefit, there were a number of promising developments.

Authors
Morse, MA
MLA Citation
Morse, MA. "American Society of Clinical Oncology - 36th Annual Meeting." IDrugs 3.8 (August 2000): 846-850.
PMID
16059792
Source
pubmed
Published In
Idrugs
Volume
3
Issue
8
Publish Date
2000
Start Page
846
End Page
850

Myxoid liposarcoma of the supraclavicular fossa.

Liposarcomas generally originate most often in the extremities or retroperitoneum, less frequently in the head and neck, and rarely in the thorax. We describe a particularly rare presentation of myxoid liposarcoma originating in the supraclavicular fossa. The mass was resected and has not recurred. We searched our pathology database for other soft-tissue tumors of the supraclavicular fossa and found no other case of sarcoma originating in this site. In addition, we performed a literature review of thoracic and neck liposarcomas to identify similar cases and discuss their clinical course.

Authors
Morse, MA; Bossen, E; D'Amico, TA; Williamson, W; Johnson, R
MLA Citation
Morse, MA, Bossen, E, D'Amico, TA, Williamson, W, and Johnson, R. "Myxoid liposarcoma of the supraclavicular fossa." Chest 117.5 (May 2000): 1518-1520.
PMID
10807849
Source
pubmed
Published In
Chest
Volume
117
Issue
5
Publish Date
2000
Start Page
1518
End Page
1520

Liver metastases from breast cancer: long-term survival after curative resection.

BACKGROUND: Liver metastases from breast cancer are associated with a poor prognosis (median survival < 6 months). A subgroup of these patients with no dissemination in other organs may benefit from surgery. Available data in the literature suggest that only in exceptional cases do these patients survive more than 2 years when given chemohormonal therapy or supportive care alone. We report the results of liver resection in patients with isolated hepatic metastases from breast cancer and evaluate the rate of long-term survival, prognostic factors, and the role of neoadjuvant high-dose chemotherapy. PATIENTS AND METHODS: Over the past decade, 17 women underwent hepatic metastectomy with curative intent for metastatic breast cancer. The follow-up was complete in each patient. The median age at the time breast cancer was diagnosed was 48 years. Neoadjuvant high-dose chemotherapy (HDC) with hematopoietic progenitor support was used in 10 patients before liver resection. Perioperative complications, long-term outcome, and prognostic factors were evaluated. RESULTS: Seven of the 17 patients are currently alive, with follow-up of up to 12 years. Four of these patients are free of tumors after 6 and 17 months and 6 and 12 years. The actuarial 5-year survival rate is 22%. One patient died postoperatively (mortality rate, 6%) of carmustine-induced fibrosing pneumonitis. There was no further major morbidity in the other patients. The liver was the primary site of recurrent disease after liver resection in 67% of the patients. Patients in whom liver metastases were found more than 1 year after resection of the primary breast cancer had a significantly better outcome than those with early (< 1 year) metastatic disease (P = .04). The type of liver resection, the lymph node status at the time of the primary breast cancer resection, and HDC had no significant impact on patient survival in this series. CONCLUSIONS: Favorable 22% long-term survival can be achieved with metastasectomy in this selected group of patients. Careful evaluation of pulmonary toxicity from carmustine and exclusion of patients with extrahepatic disease are critical. Improved survival might be achieved with better selection of patients and the use of liver-directed adjuvant therapy.

Authors
Selzner, M; Morse, MA; Vredenburgh, JJ; Meyers, WC; Clavien, PA
MLA Citation
Selzner, M, Morse, MA, Vredenburgh, JJ, Meyers, WC, and Clavien, PA. "Liver metastases from breast cancer: long-term survival after curative resection." Surgery 127.4 (April 2000): 383-389.
PMID
10776428
Source
pubmed
Published In
Surgery
Volume
127
Issue
4
Publish Date
2000
Start Page
383
End Page
389

Stem cell therapy (Aastrom Biosciences Inc).

The expansion of human stem cells and their genetic manipulation represent areas of increasing interest in the field of stem cell transplantation. Previously, stem cell transplantation has been accomplished by using cellular products obtained by large volume bone marrow or peripheral blood harvest. Difficulties with this approach include inadequate cell numbers and tumor cell contamination. Furthermore, for gene transfer modalities requiring proliferating progenitor cells, low gene expression would be expected in these products. To address these difficulties, the AastromReplicell System has been developed as a fully closed and automated system for expanding hematopoietic cells. Investigators at Aastrom have evaluated the conditions needed for optimal growth including the need for unpurified bone marrow or cord blood mononuclear cells, high cell densities, serum-containing medium and certain types of plastic surfaces. Studies have now been initiated to demonstrate the feasibility of generating enough cells to fully reconstitute hematopoiesis from small volumes of cellular progenitors. It has also been demonstrated that tumor cell contamination passively decreases during the culture period. It now remains to be shown in a direct comparison that this approach yields greater efficacy and a lower cost than transplantation with unmanipulated large volume marrow or peripheral blood stem cell products.

Authors
Morse, MA
MLA Citation
Morse, MA. "Stem cell therapy (Aastrom Biosciences Inc)." IDrugs 3.3 (March 2000): 346-353.
PMID
16103945
Source
pubmed
Published In
Idrugs
Volume
3
Issue
3
Publish Date
2000
Start Page
346
End Page
353

Clinical applications of dendritic cell vaccines.

Dendritic cells play a central role in the presentation of antigen to naïve T-cells and the induction of primary immune responses. Preclinical studies have established that dendritic cells loaded with antigens ex vivo induce potent antitumor and antiviral immune responses in vitro and in vivo. This has lead to a proliferation of clinical trials testing their effectiveness in humans, particularly with advanced malignancies. The few reported studies suggest that clinically relevant immune responses may be induced against some types of malignancies. Many questions regarding the best type of dendritic cell, degree of maturity, choice of antigen, route and schedule of administration, targeting to lymphoid tissue and use of additional adjuvants will need to be answered in preclinical and clinical studies as the field of dendritic cell-based immunotherapy progresses.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Clinical applications of dendritic cell vaccines." Curr Opin Mol Ther 2.1 (February 2000): 20-28. (Review)
PMID
11249649
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
2
Issue
1
Publish Date
2000
Start Page
20
End Page
28

Gene therapy for lung cancer.

Gene therapy is emerging as a promising modality for the treatment of lung cancer. Diverse strategies employing gene therapy for lung cancer have been investigated in vitro and in animal models, and a number of these approaches have met with promising results. Several phase I and II clinical trials have been undertaken, and early results suggest that it may be safe to administer gene therapy to lung cancer patients. It remains to be determined whether this modality will be efficacious as primary or adjunctive therapy in the setting of lung cancer.

Authors
Mosca, PJ; Morse, MA; D'Amico, TA; Crawford, J; Lyerly, HK
MLA Citation
Mosca, PJ, Morse, MA, D'Amico, TA, Crawford, J, and Lyerly, HK. "Gene therapy for lung cancer." Clin Lung Cancer 1.3 (February 2000): 218-226.
PMID
14733649
Source
pubmed
Published In
Clinical lung cancer
Volume
1
Issue
3
Publish Date
2000
Start Page
218
End Page
226

Dendritic cell-based immunization for cancer therapy.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Dendritic cell-based immunization for cancer therapy." Adv Exp Med Biol 465 (2000): 335-346. (Review)
PMID
10810637
Source
pubmed
Published In
Advances in experimental medicine and biology
Volume
465
Publish Date
2000
Start Page
335
End Page
346

On the road to effective vaccine development

Authors
Bunce, C; Morse, MA
MLA Citation
Bunce, C, and Morse, MA. "On the road to effective vaccine development." Current Opinion in Molecular Therapeutics 2.1 (2000): 18-19.
Source
scival
Published In
Current Opinion in Molecular Therapeutics
Volume
2
Issue
1
Publish Date
2000
Start Page
18
End Page
19

Theratope Biomira Inc

Authors
Morse, MA
MLA Citation
Morse, MA. "Theratope Biomira Inc." Current Opinion in Oncologic, Endocrine and Metabolic Investigational Drugs 2.4 (2000): 405-413.
Source
scival
Published In
Current Opinion in Oncologic, Endocrine and Metabolic Investigational Drugs
Volume
2
Issue
4
Publish Date
2000
Start Page
405
End Page
413

Dendritic cell (DC) reconstitution after nonmyeloablative allogeneic stem cell transplants

Non-myeloablative allogeneic peripheral blood stem cell transplants {mini-allo PBSCT) are being evaluated as a lower toxicity alternative to conventional allogeneic transplantation for harnessing graft versus tumor effects. Induction of anti-tumor immunity post-transplant requires donor derived DC be available to process and present antigen to the donor lymphocytes. Because the kinetics of DC reconstitution after mini-allo PBSCT are unknown, we have initiated a study to evaluate DC number and function in 8 donor/recipient pairs prior to the preparative regimen and at various times after PBSC reinfusion. Peripheral blood mononuclear cells (PBMC) were separated over Ficoll and stained for FACS with antibodies to CD lie, HLA DR, and CD 14 to detect myeloid DC1, or lineage markers, CD123, HLA-DR, and CD1 le to detect lymphoid DC2. To determine the number of DC that can be generated from PBMC, we cultured the plastic adherent PBMC in serum free medium containing GM-CSF (800U/ml) and IL-4 (500U/ml) for 7 days and determined the percentage of large HLA DR+ cells by FACS. Diagnoses were AML 1, NHL 4, MDS 1, ET 1, and thalassemia 1. The preparative regimen was cyclophosphamide, fludarabine, and CAMPATH-1. Donor-derived G-CSF mobilized leukaphereses were depleted of T cells with CAMPATH-1 and reinfused. Five patients have reached day 14 following reinfusion. One failed to engraft, and the remainder achieved 43-99% donor chimerism in the bone marrow by RFLP analysis. Two patients died of disease progression. The median number of CD1 lc+CD14-HLA-DR+DC was 2.3% of the recipient PBMC prior to the preparative regimen, 1.5% of the donor leukapheresis PBMC, and 0.9% of the recipient peripheral blood at day 14 (P=NS). In two recipients who had CD1 lc-CD123bright DC2 measured after transplant, they were 0% and 0.7% of the PBMC compared to 0.13% and 0.26% in the donor leukapheresis. The median yield of DC generated from PBMC was 14% in the donor leukaphereses and 17% in the recipient peripheral blood at day 14 (P=NS). Three recipients had DC yields of < 1 % prior to the preparative regimen. This preliminary data suggests that myeloid DC 1 and DC precursors are present in the peripheral blood at the time of myeloid re-engraftment two weeks after mini-allo PBSCT. We are currently evaluating a) whether these DC are of donor or recipient origin, b) whether DC numbers stabilize at subsequent time points, c) whether DC function following transplant is diminished from pre-transplant levels. These results will guide studies of anti-tumor immunization following transplantation.

Authors
Morse, MA; Rizzieri, D; Hobeika, AC; Chao, N; Lyerly, HK
MLA Citation
Morse, MA, Rizzieri, D, Hobeika, AC, Chao, N, and Lyerly, HK. "Dendritic cell (DC) reconstitution after nonmyeloablative allogeneic stem cell transplants." 2000.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2000
Start Page
305b

A comparative study of the generation of dendritic cells from mobilized peripheral blood progenitor cells of patients undergoing high-dose chemotherapy.

Immunization with ex vivo-generated, tumor antigen-loaded dendritic cells (DC) has been proposed as a strategy for reducing relapses following high-dose chemotherapy, but the ideal time and method for obtaining DC progenitors are unknown. We determined the percentage yield, phenotype, and function of DC generated over 7 days in GM-CSF and IL-4-supplemented, serum-free medium from PBMC obtained from breast cancer and lymphoma patients at the time of their initial presentation for transplant, cytokine or chemotherapy plus cytokine-mobilized leukapheresis, and following granulocyte recovery from high-dose chemotherapy. The median yield of large dendritic-like cells as a percentage of the starting number of PBMC was similar for all the mobilization strategies (11.6%-13.8%) studied and at all time points (9.9%-12.7%), except the yield was lower from the pretherapy, unmobilized peripheral blood (6.3%). The phenotype of the generated cells was similar for the various mobilization procedures, and there were no differences in allostimulatory function of the DC from any of the groups. We conclude that functional DC may be generated equally well from mobilized PBPC and PBPC obtained after high-dose chemotherapy.

Authors
Morse, MA; Vredenburgh, JJ; Lyerly, HK
MLA Citation
Morse, MA, Vredenburgh, JJ, and Lyerly, HK. "A comparative study of the generation of dendritic cells from mobilized peripheral blood progenitor cells of patients undergoing high-dose chemotherapy." J Hematother Stem Cell Res 8.6 (December 1999): 577-584.
PMID
10645764
Source
pubmed
Published In
Journal of hematotherapy & stem cell research
Volume
8
Issue
6
Publish Date
1999
Start Page
577
End Page
584
DOI
10.1089/152581699319731

Technology evaluation: Stem-cell therapy, Aastrom Biosciences Inc.

The expansion of human stem cells and their genetic manipulation represent areas of increasing interest in the field of stem cell transplantation. Previously, stem cell transplantation has been accomplished by using cellular products obtained by large volume bone marrow or peripheral blood harvest. Difficulties with this approach include inadequate cell numbers and tumor cell contamination. Furthermore, for gene transfer modalities requiring proliferating progenitor cells, low gene expression would be expected in these products. To address these difficulties, the AastromReplicell System has been developed as a fully closed and automated system for expanding hematopoietic cells. Investigators at Aastrom have evaluated the conditions needed for optimal growth including the need for unpurified bone marrow or cord blood mononuclear cells, high cell densities, serum-containing medium and certain types of plastic surfaces. Studies have now been initiated to demonstrate the feasibility of generating enough cells to fully reconstitute hematopoiesis from small volumes of cellular progenitors. It has also been demonstrated that tumor cell contamination passively decreases during the culture period. It now remains to be shown in a direct comparison that this approach yields greater efficacy and a lower cost than transplantation with unmanipulated large volume marrow or peripheral blood stem cell products.

Authors
Morse, MA
MLA Citation
Morse, MA. "Technology evaluation: Stem-cell therapy, Aastrom Biosciences Inc." Curr Opin Mol Ther 1.6 (December 1999): 745-752. (Review)
PMID
19629872
Source
pubmed
Published In
Current Opinion in Molecular Therapeutics
Volume
1
Issue
6
Publish Date
1999
Start Page
745
End Page
752

The role of IL-13 in the generation of dendritic cells in vitro.

Clinical trials of active immunotherapy strategies against viral infections and malignancies are increasingly using dendritic cells (DC) generated in vitro from peripheral blood mononuclear cells (PBMC) in media supplemented with granulocyte macrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4). Although GM-CSF appears necessary, it is not well established whether other cytokines have advantages or could replace IL-4 in clinical preparations. IL-13 is a Th2-derived cytokine that shares a variety of biologic functions with IL-4, such as inhibition of monocyte differentiation and upregulation of major histocompatibility complex (MHC) molecules on cell surfaces. In the present study, the authors compared IL-4 and IL-13 in their abilities to induce DC differentiation and found that adherent PBMC cultured in GM-CSF and IL-13 displayed features characteristic of DC generated in media containing IL-4. They formed cellular clumps and had extensive dendrites. Fluorescence-activated cell sorter analysis showed that they expressed a high level of MHC class II and the costimulatory molecule CD86, and did not express the lineage markers CD3, CD14, CD16, or CD20. They were also equally potent stimulators of allogeneic lymphocytes in the mixed lymphocyte reaction. Moreover, the authors demonstrated that they were capable of inducing antigen-specific CD8+ cytotoxic T cells efficiently.

Authors
Morse, MA; Lyerly, HK; Li, Y
MLA Citation
Morse, MA, Lyerly, HK, and Li, Y. "The role of IL-13 in the generation of dendritic cells in vitro." J Immunother 22.6 (November 1999): 506-513.
PMID
10570749
Source
pubmed
Published In
Journal of Immunotherapy
Volume
22
Issue
6
Publish Date
1999
Start Page
506
End Page
513

Overall survival or other clinical benefits from adjuvant selective intraarterial chemotherapy in patients undergoing curative liver resection for metastatic colorectal tumor.

Authors
Clavien, PA; Selzner, M; Morse, MA
MLA Citation
Clavien, PA, Selzner, M, and Morse, MA. "Overall survival or other clinical benefits from adjuvant selective intraarterial chemotherapy in patients undergoing curative liver resection for metastatic colorectal tumor." Ann Surg 230.4 (October 1999): 607-610. (Letter)
PMID
10522730
Source
pubmed
Published In
Annals of Surgery
Volume
230
Issue
4
Publish Date
1999
Start Page
607
End Page
610

Untitled

Authors
Clavien, PA; Selzner, M; Morse, MA
MLA Citation
Clavien, PA, Selzner, M, and Morse, MA. "Untitled." ANNALS OF SURGERY 230.4 (October 1999): 607-608.
Source
wos-lite
Published In
Annals of Surgery
Volume
230
Issue
4
Publish Date
1999
Start Page
607
End Page
608
DOI
10.1097/00000658-199910000-00016

Ceramide analogue B13 induces apoptosis and completely inhibits growth of liver metastases from colon cancer in vivo a new strategy for the treatment of metastatic liver disease.

Authors
Selzner, M; Morse, MA; Sindram, D; Bielawska, A; Hannun, YA; Clavien, PA
MLA Citation
Selzner, M, Morse, MA, Sindram, D, Bielawska, A, Hannun, YA, and Clavien, PA. "Ceramide analogue B13 induces apoptosis and completely inhibits growth of liver metastases from colon cancer in vivo a new strategy for the treatment of metastatic liver disease." HEPATOLOGY 30.4 (October 1999): 161A-161A.
Source
wos-lite
Published In
Hepatology
Volume
30
Issue
4
Publish Date
1999
Start Page
161A
End Page
161A

Carcinoembryonic antigen peptide-pulsed dendritic cells in patients with metastatic cancer.

Authors
Lyerly, HK; Morse, MA
MLA Citation
Lyerly, HK, and Morse, MA. "Carcinoembryonic antigen peptide-pulsed dendritic cells in patients with metastatic cancer." Clin Lung Cancer 1.1 (August 1999): 70-72.
PMID
14725754
Source
pubmed
Published In
Clinical lung cancer
Volume
1
Issue
1
Publish Date
1999
Start Page
70
End Page
72

Induction of carcinoembryonic antigen (CEA)-specific cytotoxic T-lymphocyte responses in vitro using autologous dendritic cells loaded with CEA peptide or CEA RNA in patients with metastatic malignancies expressing CEA.

The application of dendritic cells (DC) to the active immunotherapy of cancer currently relies on the generation of potent DC capable of presenting tumor antigens such as carcinoembryonic antigen (CEA). It is unknown whether the T cells of patients with advanced malignancies can be reliably stimulated against tumor antigens by their autologous DC. In this study, starting with the peripheral blood mononuclear cells (PBMC) of patients with metastatic malignancies expressing CEA, autologous DCs were generated in vitro in serum-free media supplemented with GM-CSF and IL-4. The DCs from HLA A2 positive patients were loaded with the CEA peptide CAP-1 and the DCs from HLA A2 negative patients were depleted of bystander lymphocytes and loaded with mRNA encoding CEA. The DC preparations were tested to determine their phenotype and were used to stimulate autologous PBMC twice, separated by 10-14 days. The stimulated cells were then tested for their ability to lyse CEA-expressing target cells. We successfully generated an adequate number of DC for a clinical trial from all patients. The harvested DC preparations contained 49% DC and 87% DC if depleted of bystander lymphocytes. Phenotypic analysis showed the typical pattern of CD11c+ CD40+ CD86+ HLA-DR+ CD80(low) CD83(low) CD14(low). All preparations but one were able to stimulate CEA-specific cytotoxic T-lymphocyte (CTL) activity, suggesting that the majority of patients are not anergic to CEA and possess functional DC. The CTL activity was similar for the CEA peptide and CEA RNA-loaded DC.

Authors
Nair, SK; Hull, S; Coleman, D; Gilboa, E; Lyerly, HK; Morse, MA
MLA Citation
Nair, SK, Hull, S, Coleman, D, Gilboa, E, Lyerly, HK, and Morse, MA. "Induction of carcinoembryonic antigen (CEA)-specific cytotoxic T-lymphocyte responses in vitro using autologous dendritic cells loaded with CEA peptide or CEA RNA in patients with metastatic malignancies expressing CEA." Int J Cancer 82.1 (July 2, 1999): 121-124.
PMID
10360830
Source
pubmed
Published In
International Journal of Cancer
Volume
82
Issue
1
Publish Date
1999
Start Page
121
End Page
124

A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen.

Dendritic cells (DCs), antigen-presenting cells capable of priming naive T cells to specific antigens in an HLA-restricted fashion, have been demonstrated to induce protective T cell-mediated immunity in tumor-bearing animals. We performed this study to test the safety, feasibility, and clinical response of immunizations with in vitro-generated DCs, loaded with an HLA-A2-restricted peptide fragment of the tumor antigen carcinoembryonic antigen (CEA), for the treatment of patients with advanced CEA-expressing malignancies. Cell preparations enriched for autologous DCs were generated from the patients' plastic adherent peripheral blood mononuclear cells in serum-free media supplemented with granulocyte macrophage colony-stimulating factor and interleukin-4. Within the cell preparation, 66% of the cells expressed the phenotype typical for DCs (CD86high, HLA-DRhigh, and CD14low). The DCs were loaded with the CEA peptide CAP-1 and cryopreserved. Groups of three to six patients received four weekly or biweekly i.v. infusions of the CAP-1-loaded DC in escalating dose levels of 1 x 10(7), 3 x 10(7), and 1 x 10(8) cells/dose. A subset of the patients in the last group also received intradermal injections of 1 x 10(6) DCs. There were no toxicities directly referable to the treatments. One patient had a minor response, and one had stable disease. Skin punch biopsy at DC injection sites demonstrated pleomorphic infiltrates in the three patients evaluated. We conclude that it is feasible and safe to generate and administer large numbers of previously cryopreserved DCs loaded with CAP-1 peptide to patients with advanced malignancies.

Authors
Morse, MA; Deng, Y; Coleman, D; Hull, S; Kitrell-Fisher, E; Nair, S; Schlom, J; Ryback, ME; Lyerly, HK
MLA Citation
Morse, MA, Deng, Y, Coleman, D, Hull, S, Kitrell-Fisher, E, Nair, S, Schlom, J, Ryback, ME, and Lyerly, HK. "A Phase I study of active immunotherapy with carcinoembryonic antigen peptide (CAP-1)-pulsed, autologous human cultured dendritic cells in patients with metastatic malignancies expressing carcinoembryonic antigen." Clin Cancer Res 5.6 (June 1999): 1331-1338.
PMID
10389916
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
6
Publish Date
1999
Start Page
1331
End Page
1338

Cellular and biological therapies of gastrointestinal tumors: overview of clinical trials.

Because of the high relapse rate of resected gastrointestinal malignancies and the modest responses of metastatic disease to currently available therapies, biologic agents that harness host-tumor immunologic interactions have received increased attention. Based on promising preclinical data, current clinical trials in cellular and biologic therapies are evaluating the safety and efficacy of passive immunotherapy with tumor-reactive lymphocytes activated ex vivo and active immunotherapy with peptide, viral vector, and cellular vaccines. This review will describe the background, rationale, and experimental approach of these clinical trials. Although equally promising, antibodies, gene therapies, and antiangiogenic strategies will not be discussed.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Cellular and biological therapies of gastrointestinal tumors: overview of clinical trials." Ann Surg Oncol 6.2 (March 1999): 218-223. (Review)
PMID
10082049
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
6
Issue
2
Publish Date
1999
Start Page
218
End Page
223

Migration of human dendritic cells after injection in patients with metastatic malignancies.

Present clinical studies of active immunotherapy for malignancies using dendritic cells (DCs) require elucidation of the sites where DCs localize after injection. We evaluated the pattern of distribution of in vitro-generated, antigen-loaded, human DCs labeled with indium-111 oxyquinoline after i.v., s.c., and intradermal injection. Whereas the DCs injected i.v. localized in the lungs and then redistributed to the liver, spleen, and bone marrow, they were not detected in lymph nodes or tumors. A small percentage of DCs injected intradermally migrated rapidly to the regional lymphatics in some individuals. No lymph node activity was detected after s.c. injection. Our results demonstrate that DC distribution to sites of lymphoid tissue is dramatically affected by the mode of administration.

Authors
Morse, MA; Coleman, RE; Akabani, G; Niehaus, N; Coleman, D; Lyerly, HK
MLA Citation
Morse, MA, Coleman, RE, Akabani, G, Niehaus, N, Coleman, D, and Lyerly, HK. "Migration of human dendritic cells after injection in patients with metastatic malignancies." Cancer Res 59.1 (January 1, 1999): 56-58.
PMID
9892184
Source
pubmed
Published In
Cancer Research
Volume
59
Issue
1
Publish Date
1999
Start Page
56
End Page
58

Letter to the editor [1] (multiple letters)

Authors
Clavien, PA; Selzner, M; Morse, MA; Lorenz, M; Muller, HH
MLA Citation
Clavien, PA, Selzner, M, Morse, MA, Lorenz, M, and Muller, HH. "Letter to the editor [1] (multiple letters)." Annals of Surgery 230.4 (1999): 607-610.
Source
scival
Published In
Annals of Surgery
Volume
230
Issue
4
Publish Date
1999
Start Page
607
End Page
610

Dendritic cell-based approaches to cancer immunotherapy.

Immunologic approaches to the treatment of malignancies are currently enjoying a resurgence of enthusiasm due to the discovery of tumour-associated antigens and the requirements for stimulating a tumour antigen-specific immune response. The goal of the newer strategies is to stimulate immunity against specific tumour-associated antigens, rather than to broadly, but non-specifically, stimulate the immune system. Since dendritic cells, professional antigen-presenting cells, play a central role in stimulating immune responses in vivo, there is considerable interest in immunising patients with autologous dendritic cells loaded with tumour antigens of interest. Methods for generating large numbers of dendritic cells under clinically-applicable conditions have been developed and it has been shown that they may be loaded with antigen in many different forms including proteins or peptides, RNA or DNA and cellular extracts. Ongoing research is seeking to optimise the purity, antigen loading and maturation of the dendritic cells. Phase I clinical trials have been initiated in order to study the safety and feasibility of immunisations with dendritic cells in humans with various malignancies. Phase II studies will be performed to establish which tumours and clinical scenarios will be most relevant for dendritic cell immunotherapy. Although the commercial applicability of dendritic cell-based immunotherapy has been recognised by the biotechnology industry, commercial availability of dendritic cell vaccines await phase III studies.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Dendritic cell-based approaches to cancer immunotherapy." Expert Opin Investig Drugs 7.10 (October 1998): 1617-1627.
PMID
15991905
Source
pubmed
Published In
Expert Opinion on Investigational Drugs
Volume
7
Issue
10
Publish Date
1998
Start Page
1617
End Page
1627
DOI
10.1517/13543784.7.10.1617

Optimization of the sequence of antigen loading and CD40-ligand-induced maturation of dendritic cells.

Dendritic cells (DCs), matured by CD40-ligand (CD40L), undergo marked changes in their ability to process and present antigen, resulting in augmented lymphocyte stimulatory activity. We demonstrate that the form of the tumor antigen (peptide or genetic material) used to load the DCs dictates the required sequence of antigen loading and maturation for antitumor immunotherapy. Optimal stimulation of carcinoembryonic antigen (CEA)-specific CTLs by peptide-loaded DCs occurs when DCs from cancer patients are matured with CD40L before exposure to CEA peptide, whereas optimal stimulation by RNA-transfected DCs occurs when the DCs are loaded with CEA RNA before maturation with CD40L.

Authors
Morse, MA; Lyerly, HK; Gilboa, E; Thomas, E; Nair, SK
MLA Citation
Morse, MA, Lyerly, HK, Gilboa, E, Thomas, E, and Nair, SK. "Optimization of the sequence of antigen loading and CD40-ligand-induced maturation of dendritic cells." Cancer Res 58.14 (July 15, 1998): 2965-2968.
PMID
9679955
Source
pubmed
Published In
Cancer Research
Volume
58
Issue
14
Publish Date
1998
Start Page
2965
End Page
2968

Inhibition of NNK-induced lung tumorigenesis by modulators of NNK activation.

NNK, a tobacco-specific nitrosamine, is a potent lung carcinogen in A/J mice. One possible mechanism of reducing NNK-induced lung tumorigenesis is decreased delivery of NNK to lung as a result of enhanced hepatic CYP activity. Pretreatment with 13C, a known CYP inducer, results in inhibition of tumor multiplicity, decreased DNA adducts in lung, and increased DNA adducts in liver, due to induction of hepatic activation of NNK. A more preferable means of inhibition of NNK tumorigenesis involves direct inhibition of CYP enzymes responsible for NNK activation in lung. The arylalkyl isothiocyanates PEITC, PPITC, PBITC, PPeITC, and PHITC are effective inhibitors of NNK-induced lung tumorigenicity and DNA adduction. PEITC inhibits NNK-induced lung tumors at a dose of 5 mumol/day, but not at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC are considerably more potent inhibitors than PEITC, resulting in significant reductions in tumor multiplicity at doses of 0.2 mumol/day. For these compounds, there is a good correlation between inhibition of tumor multiplicity and inhibition of pulmonary O6-methylguanine. LIM, previously shown by Wattenberg to be an effective inhibitor of NNK-induced lung tumors, and other monoterpenes are good inhibitors of NNK activation in vitro or in vivo. Thus, compounds that modulate the metabolic activation of NNK can be potent inhibitors of NNK tumorigenesis.

Authors
Morse, MA
MLA Citation
Morse, MA. "Inhibition of NNK-induced lung tumorigenesis by modulators of NNK activation." Exp Lung Res 24.4 (July 1998): 595-604.
PMID
9659585
Source
pubmed
Published In
Experimental Lung Research (Informa)
Volume
24
Issue
4
Publish Date
1998
Start Page
595
End Page
604

High-performance liquid chromatographic method for measurement of cytochrome P450-mediated metabolism of 7-ethoxy-4-trifluoromethylcoumarin.

An HPLC method for analysis of deethylation of 7-ethoxy-4-trifluoromethylcoumarin (ETFMC), a substrate of various enzymes of the cytochrome P450 superfamily, was developed. ETFMC was incubated at 37 degrees C with human hepatic microsomes or microsomes prepared from a lymphoblastoid cell line that expresses human CYP2B6. Under these conditions, the highly fluorescent metabolite 7-hydroxy-4-trifluoromethylcoumarin (HTFMC) is formed. The metabolite was analyzed by reversed-phase HPLC with fluorescence detection. The limits of detection of the metabolite were 5.0 fmol per injection, a sensitivity at least one order of magnitude greater than the standard method, which does not involve HPLC. This method will be of great utility when quantities of microsomal protein from cell lines expressing human CYP enzymes are limited.

Authors
Morse, MA; Lu, J
MLA Citation
Morse, MA, and Lu, J. "High-performance liquid chromatographic method for measurement of cytochrome P450-mediated metabolism of 7-ethoxy-4-trifluoromethylcoumarin." J Chromatogr B Biomed Sci Appl 708.1-2 (April 24, 1998): 290-293.
PMID
9653975
Source
pubmed
Published In
Journal of Chromatography B: Biomedical Sciences and Applications
Volume
708
Issue
1-2
Publish Date
1998
Start Page
290
End Page
293

CD34+CD38-lin- cord blood cells develop into dendritic cells in human thymic stromal monolayers and thymic nodules.

Thymic dendritic cells (DCs) appear to have distinct biologic and functional properties compared with DCs in other tissues. Currently, little is known about human thymic DCs because they have been difficult to isolate and culture in vitro. Here, we report that human thymic stroma can support the development of primitive human hemopoietic stem cells into mature DCs without cytokine or serum supplementation. Coculture of CD34+CD38-lineage (lin)- and CD34+CD38+lin- umbilical cord blood cells with thymic stromal monolayers induced 43 +/- 17-fold and 32 +/- 16-fold expansions, respectively, of umbilical cord blood progenitors and also generated large numbers of cells with the morphologic, phenotypic, and functional characteristics of mature DCs. These cells expressed class I and class II MHC, CD1a, CD2, CD4, CD11c, CD40, CD45, CD80, CD83, and CD86 and were potent stimulators of allogeneic T cell activation. Primitive hemopoietic progenitors also developed into mature DCs in a novel tissue culture system of thymic nodules wherein thymic epithelial cells and fibroblasts were grown in nodular aggregates in vitro. These results demonstrate that human thymic stroma efficiently supports the development of CD34+CD38-lin- cord blood cells into mature DCs. In addition, the culture conditions described in this report are useful systems for studying the ontogeny of human DCs in thymic microenvironments.

Authors
Miralles, GD; Smith, CA; Whichard, LP; Morse, MA; Haynes, BF; Patel, DD
MLA Citation
Miralles, GD, Smith, CA, Whichard, LP, Morse, MA, Haynes, BF, and Patel, DD. "CD34+CD38-lin- cord blood cells develop into dendritic cells in human thymic stromal monolayers and thymic nodules." J Immunol 160.7 (April 1, 1998): 3290-3298.
PMID
9531286
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
160
Issue
7
Publish Date
1998
Start Page
3290
End Page
3298

Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA.

Dendritic cells (DC) generated from the peripheral blood mononuclear cells of healthy individuals or from cancer patients transfected with carcinoembryonic antigen (CEA) mRNA stimulate a potent CD8+ cytotoxic T lymphocyte (CTL) response in vitro. DCs are effectively sensitized with RNA in the absence of reagents commonly used to facilitate mammalian cell transfection. RNA encoding a chimeric CEA/LAMP-1 lysosomal targeting signal enhances the induction of CEA-specific CD4+ T cells, providing a strategy to induce T-help that may be necessary to generate and/or maintain an optimal CD8+ CTL response in vivo. CEA RNA-transfected DCs also serve as effective targets in cytotoxicity assays, thus providing a general method for inducing, as well as measuring, CEA-specific CTL responses across a broad spectrum of HLA haplotypes.

Authors
Nair, SK; Boczkowski, D; Morse, M; Cumming, RI; Lyerly, HK; Gilboa, E
MLA Citation
Nair, SK, Boczkowski, D, Morse, M, Cumming, RI, Lyerly, HK, and Gilboa, E. "Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA." Nat Biotechnol 16.4 (April 1998): 364-369.
PMID
9555728
Source
pubmed
Published In
Nature Biotechnology
Volume
16
Issue
4
Publish Date
1998
Start Page
364
End Page
369
DOI
10.1038/nbt0498-364

Immunotherapy of cancer using dendritic cells.

While the promise of harnessing the immune system for a therapeutic effect has remained largely unfulfilled for many years, the discovery of the central role of dendritic cells in stimulating antigen-specific immune responses has prompted new enthusiasm for immunotherapy of malignancies. Elucidation of the pathways of dendritic cell development and trafficking, acquisition and processing of antigen, and stimulation of T cells has suggested methods for generating and antigen-loading dendritic cells for use in immunotherapy protocols. Animal models have demonstrated that dendritic cells can stimulate protective antitumor responses in vivo. Phase I clinical trials have been initiated to address the safety and feasibility of immunizations with dendritic cells in humans with various malignancies.

Authors
Morse, MA; Lyerly, HK
MLA Citation
Morse, MA, and Lyerly, HK. "Immunotherapy of cancer using dendritic cells." Cytokines Cell Mol Ther 4.1 (March 1998): 35-44. (Review)
PMID
9557215
Source
pubmed
Published In
Cytokines, Cellular and Molecular Therapy
Volume
4
Issue
1
Publish Date
1998
Start Page
35
End Page
44

Induction of primary, human antigen-specific cytotoxic T lymphocytes in vitro using dendritic cells pulsed with peptides.

Using a murine metastasis model, we have previously shown that antigen-presenting cells (APC) loaded with unfractionated peptides derived from poorly immunogenic, highly metastatic tumor cells represent a potent form of tumor vaccine. The antimetastatic effect of peptide pulsed APC could be further enhanced by pretreating the cells with antisense oligonucleotides directed against the TAP-2 gene to increase the density of specific peptide-major histocompatibility complex (MHC) class I complexes and thereby improve the APC function of the treated cells (Nair SK et al., J Immunol 1996;156:1772). In this study, we investigated whether similar strategies can be used to enhance the potency of human dendritic cells (DC) to present antigen. We show that human DC pulsed with peptides encoding known cytotoxic T-lymphocyte (CTL) epitopes stimulate both memory and primary CTL responses in vitro after two cycles of stimulation with the peptide-pulsed DC. Two approaches were used to increase the density of specific peptide-MHC complexes on the surface of DC. One approach was to inhibit transporter associated with antigen presentation (TAP) function using TAP antisense oligonucleotides. The second approach was to inhibit the endogenous generation of the peptide epitopes by pretreating the DC with a proteasome inhibitor. Treatment of DC with either TAP antisense oligonucleotides or with a proteasome inhibitor resulted in a dramatic enhancement of primary CTL induction.

Authors
Wong, C; Morse, M; Nair, SK
MLA Citation
Wong, C, Morse, M, and Nair, SK. "Induction of primary, human antigen-specific cytotoxic T lymphocytes in vitro using dendritic cells pulsed with peptides." J Immunother 21.1 (January 1998): 32-40.
PMID
9456434
Source
pubmed
Published In
Journal of Immunotherapy
Volume
21
Issue
1
Publish Date
1998
Start Page
32
End Page
40

Extrathymic stem cells develop into dendritic cells in human thymic microenvironments in vitro.

Authors
Miralles, GD; Patel, DD; FernandezCasal, M; Whichard, LP; Morse, MA; Smith, CA
MLA Citation
Miralles, GD, Patel, DD, FernandezCasal, M, Whichard, LP, Morse, MA, and Smith, CA. "Extrathymic stem cells develop into dendritic cells in human thymic microenvironments in vitro." BLOOD 90.10 (November 15, 1997): 3382-3382.
Source
wos-lite
Published In
Blood
Volume
90
Issue
10
Publish Date
1997
Start Page
3382
End Page
3382

Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy.

OBJECTIVE: The purpose of the study was to characterize the requirements in terms of precursors, developmental pathways, and media for the generation of large numbers of mature dendritic cells (DC) under conditions acceptable for use in adjuvant, active immunotherapy strategies for surgically treated malignancies. SUMMARY BACKGROUND DATA: Although limited previously by the small numbers accessible, DC-based immunotherapies for malignancy have become more realistic with the development of methods for efficiently generating larger numbers of DC from peripheral blood mononuclear cells (PBMC) in vitro, but these methods rely on clinically unacceptable culture conditions (such as inclusion of fetal bovine serum), necessitating the development of methods for generating functionally equivalent DC in serum-free conditions. METHODS: Plastic-adherent PBMC (from healthy donors and patients with cancer) were incubated for 7 days with granulocyte-macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) with and without tumor necrosis factor-alpha (TNF-alpha) in fetal bovine serum-containing and serum-free media and were analyzed by Wright's stain for morphology, flow cytometry for phenotype, and mixed lymphocyte reaction for allostimulatory function. RESULTS: Growth in either serum-containing or serum-free media supplemented with GM-CSF and IL-4 yielded a similarly heterogeneous population of cells, 6% to 10% of which had the morphology (large cells with thin projections), immunophenotype (including CD83+), and function of mature DC. Tumor necrosis factor-alpha significantly augmented the number of these mature DC, whereas preculture depletion of CD14+ PBMC virtually eliminated them. CONCLUSIONS: Generation of mature DC in the authors' serum-free clinically applicable conditions is similar to serum-containing conditions and requires CD14+ precursors, differentiation through a CD14-CD83- immature stage under the influence of GM-CSF and IL-4, and maturation into a CD83+ DC under the influence of TNF-alpha.

Authors
Morse, MA; Zhou, LJ; Tedder, TF; Lyerly, HK; Smith, C
MLA Citation
Morse, MA, Zhou, LJ, Tedder, TF, Lyerly, HK, and Smith, C. "Generation of dendritic cells in vitro from peripheral blood mononuclear cells with granulocyte-macrophage-colony-stimulating factor, interleukin-4, and tumor necrosis factor-alpha for use in cancer immunotherapy." Ann Surg 226.1 (July 1997): 6-16.
PMID
9242332
Source
pubmed
Published In
Annals of Surgery
Volume
226
Issue
1
Publish Date
1997
Start Page
6
End Page
16

Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells.

Pancreatic cancer has a poor prognosis even when complete resection can be accomplished. Recent studies have demonstrated that the immune system is capable of mounting effective tumor-specific immune responses even against "nonimmunogenic" tumors. The studies reported herein were conducted to determine if induction of tumor-specific immune responses of inhibiting in vivo pancreatic tumor growth could be achieved through active immunization with pancreatic tumor cells genetically engineered to secrete interleukin-2 (IL-2). A relevant poorly immunogenic subcutaneous model of murine ductal pancreatic cancer was first developed using an implantable tumor cell line Panc02 in C57BL/6 mice. Panc02 cells were then genetically engineered to secrete human IL-2 (Panc02/IL2). The ability of irradiated Panc02/IL2 cells to stimulate an immune response capable of rejecting a subsequent tumor challenge was first demonstrated. Ninety percent of animals vaccinated with irradiated parental Panc02 and subsequently challenged with parental Panc02 cells developed tumors by 48 days (mean tumor volume of 234 mm3) compared to only 40% (P < .05, chi square) of animals vaccinated with irradiated Panc02/IL2 and challenged with parental Panc02 (14 mm3, P < .004, tau test). The therapeutic benefit of active immunization in tumor-bearing animals was then examined. Mice with 3-day-old established subcutaneous tumors were administered a series of 4 weekly vaccinations with irradiated Panc02 or Panc02/IL2 cells. A significant reduction in tumor growth was present in those animals vaccinated with Panc02/IL2 (P < .005, tau test) versus Panc02 or saline. Animals whose established tumors regressed following vaccinations with IL-2-secreting Panc02 cells were found to have long-lasting immunity as demonstrated by rejection of a tumor challenge presented over 140 days following inoculation of the primary tumor. We conclude that an immune response capable of inhibiting established pancreatic tumors can be generated by vaccination with IL-2-secreting tumor cells. Furthermore, long-term immunological memory was established in mice that rejected the original established tumor. These studies provide preclinical evidence to support the use of cytokine gene-transduced tumor cell vaccinations in patients with pancreatic cancer.

Authors
Clary, BM; Coveney, EC; Philip, R; Blazer, DG; Morse, M; Gilboa, E; Lyerly, HK
MLA Citation
Clary, BM, Coveney, EC, Philip, R, Blazer, DG, Morse, M, Gilboa, E, and Lyerly, HK. "Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells." Cancer Gene Ther 4.2 (March 1997): 97-104.
PMID
9080118
Source
pubmed
Published In
Cancer Gene Therapy
Volume
4
Issue
2
Publish Date
1997
Start Page
97
End Page
104

Mechanism of enhancement of esophageal tumorigenesis by 6-phenylhexyl isothiocyanate.

6-Phenylhexyl isothiocyanate (PHITC) enhances esophageal tumorigenesis induced by the carcinogen N-nitrosomethylbenzylamine (NMBA) in rats while its shorter chain analog, phenethyl isothiocyanate (PEITC), inhibits NMBA-induced esophageal tumorigenesis. A significant increase in O6-methylguanine levels in esophageal DNA at 72 h after NMBA administration to rats pretreated with PHITC suggested that PHITC might enhance NMBA metabolic activation or inhibit DNA repair. To test this hypothesis, groups of 20 rats were administered PEITC or PHITC at concentrations of 0, 1.0, or 2.5 mmol/kg in modified AIN-76A diet for 2 weeks. The esophagi were removed from rats, stripped, split, and maintained in HEPES buffered saline (HBS) for assays of NMBA metabolism (n = 5 per group) or were snap frozen for DNA repair assays (n = 15 per group). The principal metabolites of NMBA produced by esophageal explants were: two unidentified peaks, benzyl alcohol (at 4 h only), and benzoic acid. Esophageal explants from PEITC-treated animals showed a significantly decreased ability to metabolize NMBA as expected. PHITC-treated animals showed a slight inhibition in the formation of most NMBA-related metabolites, rather than an overall increase in NMBA activation. This inhibition was less than that observed with PEITC. No inhibitory effects were observed on O6-alkylguanine transferase (AGT) activity in the esophagi of rats treated with 1.0 micromol/g or 2.5 micromol/g PHITC. Thus, effects of PHITC on esophageal metabolism and DNA repair do not account for the enhancement of NMBA tumorigenicity by PHITC.

Authors
Morse, MA; Lu, J; Gopalakrishnan, R; Peterson, LA; D'Ambrosio, SM; Wani, G; Stoner, GD
MLA Citation
Morse, MA, Lu, J, Gopalakrishnan, R, Peterson, LA, D'Ambrosio, SM, Wani, G, and Stoner, GD. "Mechanism of enhancement of esophageal tumorigenesis by 6-phenylhexyl isothiocyanate." Cancer Lett 112.1 (January 15, 1997): 119-125.
PMID
9029177
Source
pubmed
Published In
Cancer Letters
Volume
112
Issue
1
Publish Date
1997
Start Page
119
End Page
125

Active immunization with tumor cells transduced by a novel AAV plasmid-based gene delivery system.

Ex vivo genetically engineered cytokine-secreting tumor cell vaccines have been shown to prevent metastatic disease in animal models of lung and breast cancer. Because of the inefficiency of existing modes of gene delivery in transducing primary human tumor cells, it has been difficult to clinically apply this strategy. In this study, liposome-mediated delivery of an adeno-associated virus (AAV)-based plasmid containing the sequence for murine gamma-interferon (gamma-IFN) (pMP6A-mIFN-gamma) was used to generate cytokine-secreting murine tumor cell vaccines. High levels of gamma-IFN and elevated class I major histocompatibility complex expression after transfer of pMP6A-mIFN-gamma into the murine lung cancer cell line, D122, was demonstrated. The efficiency of gene transfer was determined by two different methods and was estimated to be 10-15%. Irradiated gamma-IFN D122 cells generated by this novel gene delivery system (D122/pMP6A-mIFN-gamma) and also by standard retroviral methods (DIF2) were administered as weekly vaccinations by intraperitoneal injection to animals bearing 7-day-old intrafootpad D122 tumors. Hindlimb amputation was performed when footpad diameters reached 7 mm, and lungs were harvested 28 days later. Animals vaccinated with gamma-IFN-secreting D122 cells produced by AAV-based plasmids delivery demonstrated a significant delay in footpad tumor growth when compared with controls and DIF2 cells. Fifty-seven percent of animals vaccinated with D122/pMP6A-mIFN-gamma were free of pulmonary metastases 28 days after amputation, significantly improved from the 0, 7, and 15% observed in animals vaccinated with irradiated parental D122 cells, irradiated D122 cells lipofected with an empty-cassette vector (pMP6A), or DIF2 cells, respectively. These results and the ability to transfer genes with this delivery system to a broad range of tumor types support its use in the generation of cytokine-secreting tumor cell vaccinations for use in clinical trials.

Authors
Clary, BM; Coveney, EC; Blazer, DG; Philip, R; Philip, M; Morse, M; Gilboa, E; Lyerly, HK
MLA Citation
Clary, BM, Coveney, EC, Blazer, DG, Philip, R, Philip, M, Morse, M, Gilboa, E, and Lyerly, HK. "Active immunization with tumor cells transduced by a novel AAV plasmid-based gene delivery system." J Immunother 20.1 (January 1997): 26-37.
PMID
9101411
Source
pubmed
Published In
Journal of Immunotherapy
Volume
20
Issue
1
Publish Date
1997
Start Page
26
End Page
37

Influence of nitroglycerin on splanchnic capacity and splanchnic capacity-cardiac output relationship.

It has been postulated, but not tested directly, that nitroglycerin's venodilatory effects attenuate cardiac output. Thus, the present study examined the importance of changes in splanchnic capacity, as assessed by scintigraphy, in the regulation of cardiac output during nitroglycerin administration in 16 anesthetized pigs under conditions of carotid sinus denervation and cervical vagotomy. With nitroglycerin administration (0.5 mg/min i.v.) for 5 min, systemic arterial pressure decreased from 115 +/- 7 to 95 +/- 7 mmHg (P < 0.0001), portal vein pressure decreased from 9.0 +/- 0.5 to 8.5 +/- 0.5 mmHg (P < 0.0001), portal flow increased from 637 +/- 49 to 668 +/- 60 ml/min (P = 0.09), and transhepatic resistance decreased from 7.5 +/- 1.5 to 6.5 +/- 1.0 mmHg.min.l-1 (P < 0.01), but cardiac output was unchanged (1,929 +/- 126 to 1,890 +/- 138 ml/min). Total splanchnic intravascular volume (VI) increased 1.6 +/- 1.0% (P < 0.05, 14 +/- 10 ml). This increase was due to an increment in extrahepatosplenic (mesenteric) VI (12.9 +/- 1.9%, P < 0.0001), since splenic VI decreased (9.6 +/- 2.8%, P < 0.0001) and hepatic VI did not change. After splenectomy, nitroglycerin infusions at doses of 0.5 and 2 mg/min were associated with increases in total splanchnic VI of 3.7 +/- 1.2% (P < 0.0001, 30 +/- 10 ml) and 7.6 +/- 1.7% (P < 0.001, 59 +/- 10 ml) due entirely to increases in mesenteric volume of 9.9 +/- 2.7% (P < 0.0001) and 16.5 +/- 1.9% (P < 0.0001), respectively, but cardiac output was unchanged at the end of infusion at either dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Authors
Morse, MA; Rutlen, DL
MLA Citation
Morse, MA, and Rutlen, DL. "Influence of nitroglycerin on splanchnic capacity and splanchnic capacity-cardiac output relationship." J Appl Physiol (1985) 76.1 (January 1994): 112-119.
PMID
8175494
Source
pubmed
Published In
Journal of applied physiology (Bethesda, Md. : 1985)
Volume
76
Issue
1
Publish Date
1994
Start Page
112
End Page
119

Selective nonoperative management of pediatric blunt splenic trauma: risk for missed associated injuries.

The spleen is the most commonly injured organ in children sustaining blunt abdominal trauma. Although accepted in pediatric patients, nonoperative management of blunt splenic trauma in adults remains controversial. A principal concern of advocates of early operation is the possibility of overlooking a second injury. To evaluate this question in a pediatric population, we reviewed the charts of 120 children who had traumatic splenic injuries and were admitted to Children's Hospital Medical Center in Cincinnati between 1982 and 1990. Splenic injuries were documented by computed tomography scans, liver/spleen scintigraphy, or during laparotomy. One hundred twelve patients (93.3%) were initially managed nonoperatively; this regimen failed in 2 patients (1.8%), in whom a late splenectomy was required for bleeding. Of 8 patients (6.7%) for whom emergency surgery was required, 4 underwent splenectomy (2 had major associated injuries), 2 underwent splenorrhaphy, and 2 required no splenic repair. Fifty-nine patients (49.2%) had associated injuries, 22 of which (18.3%) were intraabdominal. In this study, there were no missed injuries and no morbidity or mortality associated with delayed treatment. These data confirm that the majority of children with blunt splenic injury can be successfully treated without surgery, and demonstrate that selective nonoperative management of splenic injuries in children does not increase the risk of missed associated injuries.

Authors
Morse, MA; Garcia, VF
MLA Citation
Morse, MA, and Garcia, VF. "Selective nonoperative management of pediatric blunt splenic trauma: risk for missed associated injuries." Journal of pediatric surgery 29.1 (January 1994): 23-27. (Academic Article)
Source
manual
Published In
Journal of Pediatric Surgery
Volume
29
Issue
1
Publish Date
1994
Start Page
23
End Page
27

Characterization of a glucuronide metabolite of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its dose-dependent excretion in the urine of mice and rats.

Following analysis by reversed-phase HPLC, a previously uncharacterized metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was found in the urine of A/J mice treated with NNK. Treatment with beta-glucuronidase converted the metabolite to a peak that co-eluted with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). Treatment with sulfatase or beta-glucuronidase plus saccharic acid 1,4-lactone did not change the retention time of the metabolite. These data suggested that the unknown metabolite was a glucuronic acid conjugate of NNAL. Upon isolation and purification of larger quantities of the metabolite from the urine of A/J mice, CD-1 mice and F344 rats, 1H and 13C NMR and MS confirmed that the unknown metabolite was 4-(methylnitrosamino)-1-(3-pyridyl)-1-butyl beta-D-glucopyranosiduronic acid (NNAL Glu). To determine the quantitative relationship between NNK dose and NNAL Glu production and to compare the importance of glucuronidation relative to other metabolic pathways, [5-3H]NNK was administered to F344 rats and A/J mice at doses of 500-0.005 mumol/kg. At 500 mumol/kg, NNAL Glu accounted for 22% of the total urinary excretion of NNK in A/J mice, and for 8% in F344 rats 48 h after dosing. The proportions of excreted glucuronide and NNAL decreased with diminishing doses of NNK, yielding undetectable levels of each metabolite in both mice and rats at a dose of 0.005 mumol/kg NNK. Since substantial amounts of metabolites formed via alpha-hydroxylation and N-oxidation pathways were observed at the lower doses of NNK, these data demonstrate that NNAL glucuronidation is a quantitatively unimportant metabolic pathway at low doses of NNK.

Authors
Morse, MA; Eklind, KI; Toussaint, M; Amin, SG; Chung, FL
MLA Citation
Morse, MA, Eklind, KI, Toussaint, M, Amin, SG, and Chung, FL. "Characterization of a glucuronide metabolite of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its dose-dependent excretion in the urine of mice and rats." Carcinogenesis 11.10 (October 1990): 1819-1823. (Academic Article)
Source
manual
Published In
Carcinogenesis
Volume
11
Issue
10
Publish Date
1990
Start Page
1819
End Page
1823

Influence of splanchnic intravascular volume changes on cardiac output during muscarinic receptor stimulation in the anaesthetized dog.

The direct influence of systemic muscarinic receptor stimulation on total splanchnic intravascular volume and the splanchnic organs responsible for the total splanchnic volume change associated with muscarinic receptor stimulation in the animal with an intact circulation are unknown. Furthermore, the subsequent effect of these volume changes on cardiac output is not known. Thus, acetylcholine was infused at 5 micrograms kg-1 min-1 in 25 anaesthetized dogs in which nicotinic blockade of the ganglia was achieved with mecamylamine, while total and regional splanchnic intravascular volume changes were determined with a radionuclide imaging technique. Total splanchnic volume decreased by 4.9 +/- 1.0% (P less than 0.0001), splenic volume decreased by 10.3 +/- 2.0% (P less than 0.0001), hepatic volume increased by 5.8 +/- 1.4% (P less than 0.01), extrahepatosplenic volume increased by 6.6 +/- 1.6% (P less than 0.01) and cardiac output increased from 1960 +/- 190 to 2290 +/- 230 ml min-1 (P less than 0.001). After splenectomy (n = 13), the hepatic and extrahepatosplenic volume increments were abolished, and the increase in cardiac output was not attenuated (1600 +/- 260 to 2040 +/- 370 ml min-1). After subsequent evisceration (n = 5), the cardiac output increment associated with acetylcholine was still not attenuated. Acetylcholine-associated splanchnic volume changes were abolished after muscarinic receptor blockade with atropine. Thus, muscarinic receptor stimulation causes a decrease in total splanchnic volume due entirely to a decrease in splenic volume. The splanchnic volume changes do not influence cardiac output.

Authors
Morse, MA; Bell, L; Rutlen, DL
MLA Citation
Morse, MA, Bell, L, and Rutlen, DL. "Influence of splanchnic intravascular volume changes on cardiac output during muscarinic receptor stimulation in the anaesthetized dog." Acta Physiol Scand 138.3 (March 1990): 331-336.
PMID
2327262
Source
pubmed
Published In
Acta physiologica Scandinavica
Volume
138
Issue
3
Publish Date
1990
Start Page
331
End Page
336
DOI
10.1111/j.1748-1716.1990.tb08854.x
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