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Lyerly, Herbert Kim

Overview:

Positions:

George Barth Geller Professor

Surgery, Surgical Sciences
School of Medicine

Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Professor in Immunology

Immunology
School of Medicine

Affiliate,Duke Global Health Institute

Duke Global Health Institute
Institutes and Provost's Academic Units

Associate Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1983

M.D. — University of California at Los Angeles

News:

Grants:

Defining the Rules of Breast Cancer Cell Traffic Through Bone

Administered By
Medicine, Hematological Malignancies
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 09, 2017
End Date
December 31, 2021

Translational Research in Surgical Oncology

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

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 01, 1985
End Date
December 31, 2020

Labeling nanobodies with 18F residualizing labels for HER2 specific PET imaging

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 01, 2015
End Date
April 30, 2020

A Molecular Framework for Understanding DCIS

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Principal Investigator
Start Date
September 30, 2014
End Date
September 29, 2019

Viral Oncology Training Grant

Administered By
Molecular Genetics and Microbiology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1980
End Date
June 30, 2019

Mechanisms of Action and Resistance to PD-1 Immunotherapies in Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Merck
Role
Collaborator
Start Date
April 13, 2017
End Date
September 30, 2018

Inhibition of Wnt/B-Catenin Signaling in Colorectal Cancer Therapy

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 19, 2013
End Date
July 31, 2018

Duke University Program in Environmental Health

Administered By
Environmental Sciences and Policy
AwardedBy
National Institute of Environmental Health Sciences
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2018

A Cancer Rainbow Mouse for Simultaneous Assessment of Multiple Oncogenes

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
February 09, 2015
End Date
January 31, 2018

Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

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

Oncogenic Signaling Networks

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

Advancing Immunology in Dogs with Naturally-occurring Invasive Bladder Cancer, a Relevant Model to Improve Immunotherapy Across Molecular Cancer Subtypes in Humans

Administered By
Surgery, Surgical Sciences
AwardedBy
Purdue University
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

A Simple System for Early Detection of Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Arizona State University
Role
Co Investigator
Start Date
July 01, 2014
End Date
June 30, 2017

AAADV Scholars

Administered By
Surgery, Surgical Sciences
AwardedBy
Millennium Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
February 12, 2016
End Date
March 31, 2017

AAADV Scholars

Administered By
Surgery, Surgical Sciences
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
January 01, 2016
End Date
June 30, 2016

AAADV Scholars

Administered By
Surgery, Surgical Sciences
AwardedBy
Pfizer, Inc.
Role
Principal Investigator
Start Date
January 01, 2016
End Date
June 30, 2016

AAADV Workshop

Administered By
Surgery, Surgical Sciences
AwardedBy
Susan G Komen for the Cure
Role
Principal Investigator
Start Date
November 01, 2015
End Date
June 30, 2016

Transfusion Medicine and Hematology

Administered By
Medicine, Hematology
AwardedBy
National Institutes of Health
Role
Preceptor
Start Date
July 01, 1975
End Date
June 30, 2016

Cancer Biology Training Grant

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Cancer Institute
Role
Mentor
Start Date
July 01, 1993
End Date
March 31, 2016

Integrating Population and Basic Science in Cancer Research

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Advisor
Start Date
September 01, 2009
End Date
August 31, 2015

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 29, 2009
End Date
July 31, 2015

2015 Accelerating Anticancer Agent Development and Validation Workshop

Administered By
Surgery, Surgical Sciences
AwardedBy
Susan G Komen for the Cure
Role
Principal Investigator
Start Date
January 13, 2015
End Date
July 08, 2015

A Cancer Rainbow Mouse for the Simultaneous Assessment of Multiple Oncogenes

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 12, 2012
End Date
February 28, 2015

Administrative Supplement for Recruitment of New Faculty

Administered By
Duke Cancer Institute
AwardedBy
National Cancer Institute
Role
Principal Investigator
Start Date
September 30, 2009
End Date
September 29, 2011

Immunotherapy with High Frequency, CEA Specific

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 19, 2000
End Date
June 30, 2011

SPORE in Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1998
End Date
June 30, 2010

Cancer Center Core Grant Supplement - Accelerating Anticancer Agent Dev Workshop

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2006
End Date
December 31, 2009

Cancer Center Core Grant Supplement - Accelerating Anticancer Agent Dev Workshop

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 13, 2005
End Date
December 31, 2009

Targeting hCG-beta for Breast Cancer Immunotherapy

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

Developing Biomarker-Based Prognostics in Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Sponsor
Start Date
July 06, 2004
End Date
June 30, 2009

Vaccination with Regulatory T Cell Depletion

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

Phase II trial of Cetuximab & Carboplatin in Basal-like Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Markers of short term breast cancer risk in FNA

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Novel Biomarkers for Aromatase Inhibitor Therapy

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1995
End Date
June 30, 2008

Biomarker Studies for Novel Anti-Cancer Agents

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

Dendritic Cell Based Immunotherapy

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 25, 2002
End Date
July 31, 2007

Immunotherapy using peptide MHC tetramer isolated Tcells

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

Immunologic Correlates of Effective Immunizations for Cancer Vaccines

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
July 30, 2001
End Date
December 31, 2006

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

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

Phase II Trial of Estradiol Therapy for Advanced Breast Cancer

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2003
End Date
December 31, 2005

Mentored Oriented Research Career Development Award

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 2000
End Date
April 30, 2005

Cancer Center Core Grant - CURE Supplment

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2003
End Date
December 31, 2004

Immunotherapy of Prostate Cancer with Tumor Vaccines

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Sponsor
Start Date
September 01, 1999
End Date
August 31, 2004

RNA Transfected Dendritic Cells for Cancer Immunotherapy

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1999
End Date
March 31, 2004

Dexasome Based Immunotherapy of Lung Cancer

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

Immunotherapy with TRICOM Modified Dendritic Cells

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

Cytomation MoFlo High Performance Flow Cytometer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2002
End Date
February 28, 2003

Dendritic Cell Immunotherapy For Breast Cancer

AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1998
End Date
June 30, 2000

Cancer Immunotherapy With Rna Pulsed Dendritic Cells

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1998
End Date
August 31, 1999

Immunotherapy With Peptide Pulsed Dendritic Cell

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1996
End Date
August 31, 1999

Immunotherapy With Peptide Pulsed Dendritic Cells

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1996
End Date
August 31, 1999

Viral Control And Immune Reconstitution In Hiv Infection

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1996
End Date
August 31, 1999

Viral Control & Immune Reconstitution In Hiv Infection

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1999

Immunotherapy Of Breast Cance5 With Gene Modified Tumor

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1995
End Date
August 31, 1999

Immunotherapy Of Breast Cancer With Gene Modified Tumor

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 1995
End Date
August 31, 1999

DUMC Aids Malignancy Program

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
July 31, 1999

Dumc Aids Malignancy Program

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
July 31, 1999

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Spore In Breast Cancer

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 30, 1995
End Date
August 31, 1998

Surrogate Markers Of Tumor Specific Immunity

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 24, 1994
End Date
May 31, 1998

Preclinical Development Of Rna Decoys

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
May 01, 1994
End Date
January 31, 1998

Adoptive Immunotherapy For Aids Lymphoma

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1993
End Date
August 31, 1996

Cellular Immunity Against Post-Transplant Lymphoma

Administered By
Surgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 1992
End Date
September 29, 1994
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Publications:

Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled Receptor-5 diminishes cell fitness.

The leucine-rich G protein-coupled receptor-5 (LGR5) is expressed in adult tissue stem cells of many epithelia and its overexpression is negatively correlated with cancer prognosis. LGR5 potentiates WNT/β-catenin signaling through its unique constitutive internalization property that clears negative regulators of the WNT-receptor complex from the membrane. However, both the mechanism and physiological relevance of LGR5 internalization is unclear. Therefore, a natural product library was screened to discover LGR5 internalization inhibitors and gain mechanistic insight into LGR5 internalization. The plant lignan justicidin B, blocked the constitutive internalization of LGR5. Justicidin B is structurally similar to more potent vacuolar-type H+-ATPase (vATPase) inhibitors, which all inhibited LGR5 internalization by blocking clathrin-mediated endocytosis. We then tested the physiological relevance of LGR5 internalization blockade in vivo. A LGR5-rainbow (LBOW) mouse line was engineered to express three different LGR5 isoforms along with unique fluorescent protein lineage reporters in the same mouse. In this manner, the effects of each isoform on cell fate can be simultaneously assessed through simple fluorescent imaging for each lineage reporter. LBOW mice express three different forms of LGR5, which includes a wild-type form that constitutively internalizes and two mutant forms whose internalization properties have been compromised by genetic perturbations within the carboxyl-terminal tail. LBOW was activated in the intestinal epithelium and a year-long lineage tracing course revealed that genetic blockade of LGR5 internalization diminished cell fitness. Together these data provide proof-of-concept genetic evidence that blocking the clathrin-mediated endocytosis of LGR5 could be used to pharmacologically control cell behavior.

Authors
Snyder, JC; Rochelle, LK; Ray, C; Pack, TF; Bock, CB; Lubkov, V; Lyerly, HK; Waggoner, AS; Barak, LS; Caron, MG
MLA Citation
Snyder, JC, Rochelle, LK, Ray, C, Pack, TF, Bock, CB, Lubkov, V, Lyerly, HK, Waggoner, AS, Barak, LS, and Caron, MG. "Inhibiting clathrin-mediated endocytosis of the leucine-rich G protein-coupled Receptor-5 diminishes cell fitness." The Journal of biological chemistry (March 8, 2017).
PMID
28275053
Source
epmc
Published In
The Journal of biological chemistry
Publish Date
2017
DOI
10.1074/jbc.m116.756635

Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.

The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

Authors
Mook, RA; Ren, X-R; Wang, J; Piao, H; Barak, LS; Kim Lyerly, H; Chen, W
MLA Citation
Mook, RA, Ren, X-R, Wang, J, Piao, H, Barak, LS, Kim Lyerly, H, and Chen, W. "Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis." Bioorganic & medicinal chemistry 25.6 (March 2017): 1804-1816.
PMID
28233680
Source
epmc
Published In
Bioorganic & Medicinal Chemistry
Volume
25
Issue
6
Publish Date
2017
Start Page
1804
End Page
1816
DOI
10.1016/j.bmc.2017.01.046

A Fluorescent Hsp90 Probe Demonstrates the Unique Association between Extracellular Hsp90 and Malignancy in Vivo.

Extracellular expression of heat shock protein 90 (eHsp90) by tumor cells is correlated with malignancy. Development of small molecule probes that can detect eHsp90 in vivo may therefore have utility in the early detection of malignancy. We synthesized a cell impermeable far-red fluorophore-tagged Hsp90 inhibitor to target eHsp90 in vivo. High resolution confocal and lattice light sheet microscopy show that probe-bound eHsp90 accumulates in punctate structures on the plasma membrane of breast tumor cells and is actively internalized. The extent of internalization correlates with tumor cell aggressiveness, and this process can be induced in benign cells by overexpressing p110HER2. Whole body cryoslicing, imaging, and histology of flank and spontaneous tumor-bearing mice strongly suggests that eHsp90 expression and internalization is a phenomenon unique to tumor cells in vivo and may provide an "Achilles heel" for the early diagnosis of metastatic disease and targeted drug delivery.

Authors
Crowe, LB; Hughes, PF; Alcorta, DA; Osada, T; Smith, AP; Totzke, J; Loiselle, DR; Lutz, ID; Gargesha, M; Roy, D; Roques, J; Darr, D; Lyerly, HK; Spector, NL; Haystead, TAJ
MLA Citation
Crowe, LB, Hughes, PF, Alcorta, DA, Osada, T, Smith, AP, Totzke, J, Loiselle, DR, Lutz, ID, Gargesha, M, Roy, D, Roques, J, Darr, D, Lyerly, HK, Spector, NL, and Haystead, TAJ. "A Fluorescent Hsp90 Probe Demonstrates the Unique Association between Extracellular Hsp90 and Malignancy in Vivo." ACS chemical biology (February 2017).
PMID
28103010
Source
epmc
Published In
ACS Chemical Biology
Publish Date
2017
DOI
10.1021/acschembio.7b00006

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-.
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

Abstract 3417: Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy

Authors
Song, Q; Ren, J; Yu, J; Wang, X; Zhou, X; Lyerly, HK
MLA Citation
Song, Q, Ren, J, Yu, J, Wang, X, Zhou, X, and Lyerly, HK. "Abstract 3417: Peripheral CD8+CD28-suppressive T lymphocytes act as a prognosticator among breast cancer patients with adoptive T-cell immunotherapy." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
3417
End Page
3417
DOI
10.1158/1538-7445.AM2016-3417

Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET.

The human growth factor receptor type 2 (HER2) is overexpressed in breast as well as other types of cancer. Immuno-PET, a noninvasive imaging procedure that could assess HER2 status in both primary and metastatic lesions simultaneously, could be a valuable tool for optimizing application of HER2-targeted therapies in individual patients. Herein, we have evaluated the tumor-targeting potential of the 5F7 anti-HER2 Nanobody (single-domain antibody fragment; ∼13 kDa) after (18)F labeling by 2 methods.The 5F7 Nanobody was labeled with (18)F using the novel residualizing label N-succinimidyl 3-((4-(4-(18)F-fluorobutyl)-1H-1,2,3-triazol-1-yl)methyl)-5-(guanidinomethyl)benzoate ((18)F-SFBTMGMB; (18)F-RL-I) and also via the most commonly used (18)F protein-labeling prosthetic agent N-succinimidyl 3-(18)F-fluorobenzoate ((18)F-SFB). For comparison, 5F7 Nanobody was also labeled using the residualizing radioiodination agent N-succinimidyl 4-guanidinomethyl-3-(125)I-iodobenzoate ((125)I-SGMIB). Paired-label ((18)F/(125)I) internalization assays and biodistribution studies were performed on HER2-expressing BT474M1 breast carcinoma cells and in mice with BT474M1 subcutaneous xenografts, respectively. Small-animal PET/CT imaging of 5F7 Nanobody labeled using (18)F-RL-I also was performed.Internalization assays indicated that intracellularly retained radioactivity for (18)F-RL-I-5F7 was similar to that for coincubated (125)I-SGMIB-5F7, whereas that for (18)F-SFB-5F7 was lower than coincubated (125)I-SGMIB-5F7 and decreased with time. BT474M1 tumor uptake of (18)F-RL-I-5F7 was 28.97 ± 3.88 percentage injected dose per gram of tissue (%ID/g) at 1 h and 36.28 ± 14.10 %ID/g at 2 h, reduced by more than 90% on blocking with trastuzumab, indicating HER2 specificity of uptake, and was also 26%-28% higher (P < 0.05) than that of (18)F-SFB-5F7. At 2 h, the tumor-to-blood ratio for (18)F-RL-I-5F7 (47.4 ± 13.1) was significantly higher (P < 0.05) than for (18)F-SFB-5F7 (25.4 ± 10.3); however, kidney uptake was 28-36-fold higher for (18)F-RL-I-5F7.(18)F-RL-I-5F7 is a promising tracer for evaluating HER2 status by immuno-PET; however, in settings in which renal background is problematic, strategies for reducing its kidney uptake may be needed.

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Weitzel, D; Osada, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Weitzel, D, Osada, T, Lyerly, HK, and Zalutsky, MR. "Preclinical Evaluation of 18F-Labeled Anti-HER2 Nanobody Conjugates for Imaging HER2 Receptor Expression by Immuno-PET." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57.6 (June 2016): 967-973.
PMID
26912425
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
57
Issue
6
Publish Date
2016
Start Page
967
End Page
973
DOI
10.2967/jnumed.115.171306

WE-FG-BRA-01: Cancer Treatment Utilizing Photo-Activation of Psoralen with KV X-Rays.

This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with immunogenic anti-cancer potential. Psoralen therapies have been limited due to the requirement for psoralen activation by UVA light. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and reradiate (phosphoresce) at UV wavelengths.The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry to investigate treatment induced apoptosis. Methylene blue staining, and WST assays were also used. X-PACT was then evaluated in an in-vivo pilot study on BALBc mice with syngeneic 4T1 tumors, including control arms for X-PACT components. Analysis focused on tumor growth delay.A multivariable regression analysis of 36 independent in-vitro irradiation experiments demonstrated that X-PACT induces significant tumor cell apoptosis and cytotoxicity on all three tumor cell lines in-vitro (p<0.0001). Neither psoralen nor phosphor alone had a strongly significant effect. The in-vivo studies show a pronounced tumor growth delay when compared to controls (42% reduction at 25 days, p=0.0002).These studies demonstrate for the first time a therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation generate UVA light in-situ (including deep seated lesions) which in-turn photo-activates powerful anticancer therapeutics which may lead to short and long term therapeutic effect. This work was supported by Immunolight Llc.

Authors
Oldham, M; Yoon, S; Meng, B; Fathi, Z; Beyer, W; Adamson, J; Alcorta, D; Osada, T; Lyerly, K; Dewhirst, M; Fecci, P; Walder, H; Spector, N
MLA Citation
Oldham, M, Yoon, S, Meng, B, Fathi, Z, Beyer, W, Adamson, J, Alcorta, D, Osada, T, Lyerly, K, Dewhirst, M, Fecci, P, Walder, H, and Spector, N. "WE-FG-BRA-01: Cancer Treatment Utilizing Photo-Activation of Psoralen with KV X-Rays." Medical physics 43.6 (June 2016): 3823-.
PMID
28047541
Source
epmc
Published In
Medical physics
Volume
43
Issue
6
Publish Date
2016
Start Page
3823
DOI
10.1118/1.4957901

Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

Authors
Price, TT; Burness, ML; Sivan, A; Warner, MJ; Cheng, R; Lee, CH; Olivere, L; Comatas, K; Magnani, J; Kim Lyerly, H; Cheng, Q; McCall, CM; Sipkins, DA
MLA Citation
Price, TT, Burness, ML, Sivan, A, Warner, MJ, Cheng, R, Lee, CH, Olivere, L, Comatas, K, Magnani, J, Kim Lyerly, H, Cheng, Q, McCall, CM, and Sipkins, DA. "Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone." Science translational medicine 8.340 (May 2016): 340ra73-.
PMID
27225183
Source
epmc
Published In
Science Translational Medicine
Volume
8
Issue
340
Publish Date
2016
Start Page
340ra73
DOI
10.1126/scitranslmed.aad4059

Abstract P4-09-16: A monoclonal antibody with exceptional specificity across major breast cancer subtypes

Authors
Das Roy, L; Zhou, R; Dillon, L; Moore, LJ; Puri, R; Marks, JR; Lyerly, HK; Mukherjee, P
MLA Citation
Das Roy, L, Zhou, R, Dillon, L, Moore, LJ, Puri, R, Marks, JR, Lyerly, HK, and Mukherjee, P. "Abstract P4-09-16: A monoclonal antibody with exceptional specificity across major breast cancer subtypes." February 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
4 Supplement
Publish Date
2016
Start Page
P4-09-16
End Page
P4-09-16
DOI
10.1158/1538-7445.SABCS15-P4-09-16

Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45).

The recent immunotherapy treatment on triple-negative breast cancer (TNBC) leads to the breakthrough assignation. In this study, we have tried the new combinations of specific chemo with DC-CIKs immunotherapy to treat those patients.Twenty-three metastatic anthracyclines and taxanes pretreated TNBC younger (mean 41.5 years) patients were initially mobilized with cyclophosphamide (3 g/m(2)) for the preparation of CD34(+) peripheral blood mononuclear cells as the resources for generating DC/CIKs and marrow function supports. All cases were subsequently experienced 2 cycles of chemotherapy with cyclophosphamide 3 g/m(2), thiotepa 150 mg/m(2), and carboplatin AUC = 6, Q4w. The patients then received 3 infusions of DC-CIKs at the chemo intervals and followed by maintenance therapy with oral cyclophosphamide 50 mg daily. The endpoints were progression-free survival and overall survival.The partial response rate was 13.0 %, stable and progressive disease rates were 56.5 and 30.4 %, respectively. The median PFS was 13.5 months (95 % confidence interval (CI) 10.1-16.9 months) and OS was 15.2 months (95 % CI 12.5-18.1 months). The most common serious adverse events were neutropenia (100.0 %) and anemia (69.7 %) but without treatment-related mortality.These data suggested that such combination therapy model be effective and safe for younger metastatic TNBC exposure to previous anthracyclines and taxanes based adjuvant chemotherapy.

Authors
Wang, X; Ren, J; Zhang, J; Yan, Y; Jiang, N; Yu, J; Di, L; Song, G; Che, L; Jia, J; Zhou, X; Yang, H; Lyerly, HK
MLA Citation
Wang, X, Ren, J, Zhang, J, Yan, Y, Jiang, N, Yu, J, Di, L, Song, G, Che, L, Jia, J, Zhou, X, Yang, H, and Lyerly, HK. "Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged <45)." Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 18.1 (January 2016): 82-87.
PMID
26266766
Source
epmc
Published In
Clinical and Translational Oncology
Volume
18
Issue
1
Publish Date
2016
Start Page
82
End Page
87
DOI
10.1007/s12094-015-1339-2

Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials.

The efficacy of PD-1/PD-L1 targeted therapies in addition to anti-CTLA-4 solidifies immunotherapy as a modality to add to the anticancer arsenal. Despite raising the bar of clinical efficacy, immunologically targeted agents raise new challenges to conventional drug development paradigms by highlighting the limited relevance of assessing standard pharmacokinetics (PK) and pharmacodynamics (PD). Specifically, systemic and intratumoral immune effects have not consistently correlated with standard relationships between systemic dose, toxicity, and efficacy for cytotoxic therapies. Hence, PK and PD paradigms remain inadequate to guide the selection of doses and schedules, both starting and recommended Phase 2 for immunotherapies. The promise of harnessing the immune response against cancer must also be considered in light of unique and potentially serious toxicities. Refining immune endpoints to better inform clinical trial design represents a high priority challenge. The Cancer Immunotherapy Trials Network investigators review the immunodynamic effects of specific classes of immunotherapeutic agents to focus immune assessment modalities and sites, both systemic and importantly intratumoral, which are critical to the success of the rapidly growing field of immuno-oncology.

Authors
Kohrt, HE; Tumeh, PC; Benson, D; Bhardwaj, N; Brody, J; Formenti, S; Fox, BA; Galon, J; June, CH; Kalos, M; Kirsch, I; Kleen, T; Kroemer, G; Lanier, L; Levy, R; Lyerly, HK; Maecker, H; Marabelle, A; Melenhorst, J; Miller, J; Melero, I; Odunsi, K; Palucka, K; Peoples, G; Ribas, A; Robins, H; Robinson, W; Serafini, T; Sondel, P; Vivier, E; Weber, J; Wolchok, J; Zitvogel, L; Disis, ML; Cheever, MA
MLA Citation
Kohrt, HE, Tumeh, PC, Benson, D, Bhardwaj, N, Brody, J, Formenti, S, Fox, BA, Galon, J, June, CH, Kalos, M, Kirsch, I, Kleen, T, Kroemer, G, Lanier, L, Levy, R, Lyerly, HK, Maecker, H, Marabelle, A, Melenhorst, J, Miller, J, Melero, I, Odunsi, K, Palucka, K, Peoples, G, Ribas, A, Robins, H, Robinson, W, Serafini, T, Sondel, P, Vivier, E, Weber, J, Wolchok, J, Zitvogel, L, Disis, ML, and Cheever, MA. "Immunodynamics: a cancer immunotherapy trials network review of immune monitoring in immuno-oncology clinical trials." Journal for immunotherapy of cancer 4 (January 2016): 15-. (Review)
PMID
26981245
Source
epmc
Published In
Journal for ImmunoTherapy of Cancer
Volume
4
Publish Date
2016
Start Page
15
DOI
10.1186/s40425-016-0118-0

X-Ray Psoralen Activated Cancer Therapy (X-PACT).

This work investigates X-PACT (X-ray Psoralen Activated Cancer Therapy): a new approach for the treatment of solid cancer. X-PACT utilizes psoralen, a potent anti-cancer therapeutic with current application to proliferative disease and extracorporeal photopheresis (ECP) of cutaneous T Cell Lymphoma. An immunogenic role for light-activated psoralen has been reported, contributing to long-term clinical responses. Psoralen therapies have to-date been limited to superficial or extracorporeal scenarios due to the requirement for psoralen activation by UVA light, which has limited penetration in tissue. X-PACT solves this challenge by activating psoralen with UV light emitted from novel non-tethered phosphors (co-incubated with psoralen) that absorb x-rays and re-radiate (phosphoresce) at UV wavelengths. The efficacy of X-PACT was evaluated in both in-vitro and in-vivo settings. In-vitro studies utilized breast (4T1), glioma (CT2A) and sarcoma (KP-B) cell lines. Cells were exposed to X-PACT treatments where the concentrations of drug (psoralen and phosphor) and radiation parameters (energy, dose, and dose rate) were varied. Efficacy was evaluated primarily using flow cell cytometry in combination with complimentary assays, and the in-vivo mouse study. In an in-vitro study, we show that X-PACT induces significant tumor cell apoptosis and cytotoxicity, unlike psoralen or phosphor alone (p<0.0001). We also show that apoptosis increases as doses of phosphor, psoralen, or radiation increase. Finally, in an in-vivo pilot study of BALBc mice with syngeneic 4T1 tumors, we show that the rate of tumor growth is slower with X-PACT than with saline or AMT + X-ray (p<0.0001). Overall these studies demonstrate a potential therapeutic effect for X-PACT, and provide a foundation and rationale for future studies. In summary, X-PACT represents a novel treatment approach in which well-tolerated low doses of x-ray radiation are delivered to a specific tumor site to generate UVA light which in-turn unleashes both short- and potentially long-term antitumor activity of photo-active therapeutics like psoralen.

Authors
Oldham, M; Yoon, P; Fathi, Z; Beyer, WF; Adamson, J; Liu, L; Alcorta, D; Xia, W; Osada, T; Liu, C; Yang, XY; Dodd, RD; Herndon, JE; Meng, B; Kirsch, DG; Lyerly, HK; Dewhirst, MW; Fecci, P; Walder, H; Spector, NL
MLA Citation
Oldham, M, Yoon, P, Fathi, Z, Beyer, WF, Adamson, J, Liu, L, Alcorta, D, Xia, W, Osada, T, Liu, C, Yang, XY, Dodd, RD, Herndon, JE, Meng, B, Kirsch, DG, Lyerly, HK, Dewhirst, MW, Fecci, P, Walder, H, and Spector, NL. "X-Ray Psoralen Activated Cancer Therapy (X-PACT)." PloS one 11.9 (January 2016): e0162078-.
Website
http://hdl.handle.net/10161/13034
PMID
27583569
Source
epmc
Published In
PloS one
Volume
11
Issue
9
Publish Date
2016
Start Page
e0162078
DOI
10.1371/journal.pone.0162078

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.
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

The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa.

This study investigated interactive effects of CYP2B6 genotypes and liver metastasis on the prognosis of metastatic breast cancer patients who received combined chemotherapy of docetaxel and thiotepa. Totally 153 patients were retrospectively genotyped rs8192719 (c.1294 + 53C > T) and rs2279343 (c.785A > G). Kaplan-Meier method and Cox Proportional Hazard Regression model were used to estimate the survival. Patients with liver metastasis had worsen prognosis, conferring a 2.26-fold high risk of progression and 1.93-fold high risk of death (p < 0.05). Both CT/TT genotype of rs8192719 (c.1294 +  3C > T) and AG genotype of rs2279343 (c.785A > G) prolonged survival (p < 0.05). Furthermore, among liver metastatic patients, AG genotype of rs2279343 (c.785A > G) was associated with a 47% reduced risk of death and a 6-month-longer overall survival (p < 0.05). Among non-liver metastatic patients, hazard ratios of CT/TT genotype of rs8192719 (c.1294 + 53C > T) were 0.45 for progression and 0.40 for death; and the corresponding survival was improved by 6 months and 16 months, respectively (p < 0.05). Genotypes of CYP2B6 had an interaction with clinical efficacy of docetaxel and thiotepa on metastatic breast cancer patients; and metastatic sites also affected clinical responses. Further therapies should take into account of chemotherapy regimen, genotypes of metabolizing enzymes and metastatic sites for the particular subpopulation.

Authors
Song, Q; Zhou, X; Yu, J; Dong, N; Wang, X; Yang, H; Ren, J; Lyerly, HK
MLA Citation
Song, Q, Zhou, X, Yu, J, Dong, N, Wang, X, Yang, H, Ren, J, and Lyerly, HK. "The prognostic values of CYP2B6 genetic polymorphisms and metastatic sites for advanced breast cancer patients treated with docetaxel and thiotepa." Scientific reports 5 (November 25, 2015): 16775-.
PMID
26602960
Source
epmc
Published In
Scientific Reports
Volume
5
Publish Date
2015
Start Page
16775
DOI
10.1038/srep16775

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities.93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded.GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity.These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Authors
Zhou, X; Wang, X; Song, Q; Yang, H; Zhu, X; Yu, J; Song, G; Di, L; Ren, J; Shao, H; Lyerly, HK
MLA Citation
Zhou, X, Wang, X, Song, Q, Yang, H, Zhu, X, Yu, J, Song, G, Di, L, Ren, J, Shao, H, and Lyerly, HK. "Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy." International journal of clinical pharmacology and therapeutics 53.11 (November 2015): 914-922.
PMID
26396136
Source
epmc
Published In
International journal of clinical pharmacology and therapeutics
Volume
53
Issue
11
Publish Date
2015
Start Page
914
End Page
922
DOI
10.5414/cp202391

IMPACTS OF CEREBROVASCULAR AND NEURODEGENERATIVE DISEASES ON SURVIVAL OF LUNG CANCER PATIENTS

MLA Citation
"IMPACTS OF CEREBROVASCULAR AND NEURODEGENERATIVE DISEASES ON SURVIVAL OF LUNG CANCER PATIENTS." The Gerontologist 55.Suppl_2 (November 2015): 496-496.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
496
End Page
496
DOI
10.1093/geront/gnv214.03

LONG-TERM DYNAMICS OF RESPIRATORY, CARDIO- AND CEREBROVASCULAR DEATH RATES AMONG OLDER ADULTS AND IMPROVING AIR QUALITY

MLA Citation
"LONG-TERM DYNAMICS OF RESPIRATORY, CARDIO- AND CEREBROVASCULAR DEATH RATES AMONG OLDER ADULTS AND IMPROVING AIR QUALITY." The Gerontologist 55.Suppl_2 (November 2015): 282-282.
Source
crossref
Published In
The Gerontologist
Volume
55
Issue
Suppl_2
Publish Date
2015
Start Page
282
End Page
282
DOI
10.1093/geront/gnv581.06

An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status

Authors
Vaidyanathan, G; McDougald, D; Choi, J; Koumarianou, E; Pruszynski, M; Osada, T; Lyerly, H; Lahoutte, T; Zalutsky, MR
MLA Citation
Vaidyanathan, G, McDougald, D, Choi, J, Koumarianou, E, Pruszynski, M, Osada, T, Lyerly, H, Lahoutte, T, and Zalutsky, MR. "An Anti-HER2 Nanobody Labeled with 18F Using a Residualizing Label for Assessing HER2 Status." October 2015.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
42
Publish Date
2015
Start Page
S102
End Page
S102

Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.

The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

Authors
Mook, RA; Wang, J; Ren, X-R; Chen, M; Spasojevic, I; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Mook, RA, Wang, J, Ren, X-R, Chen, M, Spasojevic, I, Barak, LS, Lyerly, HK, and Chen, W. "Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure." Bioorganic & medicinal chemistry 23.17 (September 2015): 5829-5838.
PMID
26272032
Source
epmc
Published In
Bioorganic & Medicinal Chemistry
Volume
23
Issue
17
Publish Date
2015
Start Page
5829
End Page
5838
DOI
10.1016/j.bmc.2015.07.001

Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche

Authors
Price, TT; Lee, CH; Cheng, Q; Lyerly, HK; Fogler, WE; Magnani, JL; Sipkins, DA
MLA Citation
Price, TT, Lee, CH, Cheng, Q, Lyerly, HK, Fogler, WE, Magnani, JL, and Sipkins, DA. "Abstract 3212: Metastatic breast cancer cell communication within a pro-dormancy bone marrow niche." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
3212
End Page
3212
DOI
10.1158/1538-7445.AM2015-3212

Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies.

As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered.The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health.Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second-generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened.The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years.Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality.

Authors
Song, Q-K; Wang, X-L; Zhou, X-N; Yang, H-B; Li, Y-C; Wu, J-P; Ren, J; Lyerly, HK
MLA Citation
Song, Q-K, Wang, X-L, Zhou, X-N, Yang, H-B, Li, Y-C, Wu, J-P, Ren, J, and Lyerly, HK. "Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies." The oncologist 20.7 (July 2015): 773-779.
PMID
26001390
Source
epmc
Published In
The oncologist
Volume
20
Issue
7
Publish Date
2015
Start Page
773
End Page
779
DOI
10.1634/theoncologist.2014-0351

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

Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions.

An increasing number of studies suggest an important role of host immunity as a barrier to tumor formation and progression. Complex mechanisms and multiple pathways are involved in evading innate and adaptive immune responses, with a broad spectrum of chemicals displaying the potential to adversely influence immunosurveillance. The evaluation of the cumulative effects of low-dose exposures from the occupational and natural environment, especially if multiple chemicals target the same gene(s) or pathway(s), is a challenge. We reviewed common environmental chemicals and discussed their potential effects on immunosurveillance. Our overarching objective was to review related signaling pathways influencing immune surveillance such as the pathways involving PI3K/Akt, chemokines, TGF-β, FAK, IGF-1, HIF-1α, IL-6, IL-1α, CTLA-4 and PD-1/PDL-1 could individually or collectively impact immunosurveillance. A number of chemicals that are common in the anthropogenic environment such as fungicides (maneb, fluoxastrobin and pyroclostrobin), herbicides (atrazine), insecticides (pyridaben and azamethiphos), the components of personal care products (triclosan and bisphenol A) and diethylhexylphthalate with pathways critical to tumor immunosurveillance. At this time, these chemicals are not recognized as human carcinogens; however, it is known that they these chemicalscan simultaneously persist in the environment and appear to have some potential interfere with the host immune response, therefore potentially contributing to promotion interacting with of immune evasion mechanisms, and promoting subsequent tumor growth and progression.

Authors
Kravchenko, J; Corsini, E; Williams, MA; Decker, W; Manjili, MH; Otsuki, T; Singh, N; Al-Mulla, F; Al-Temaimi, R; Amedei, A; Colacci, AM; Vaccari, M; Mondello, C; Scovassi, AI; Raju, J; Hamid, RA; Memeo, L; Forte, S; Roy, R; Woodrick, J; Salem, HK; Ryan, EP; Brown, DG; Bisson, WH; Lowe, L; Lyerly, HK
MLA Citation
Kravchenko, J, Corsini, E, Williams, MA, Decker, W, Manjili, MH, Otsuki, T, Singh, N, Al-Mulla, F, Al-Temaimi, R, Amedei, A, Colacci, AM, Vaccari, M, Mondello, C, Scovassi, AI, Raju, J, Hamid, RA, Memeo, L, Forte, S, Roy, R, Woodrick, J, Salem, HK, Ryan, EP, Brown, DG, Bisson, WH, Lowe, L, and Lyerly, HK. "Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions." Carcinogenesis 36 Suppl 1 (June 2015): S111-S127. (Review)
PMID
26002081
Source
epmc
Published In
Carcinogenesis
Volume
36 Suppl 1
Publish Date
2015
Start Page
S111
End Page
S127
DOI
10.1093/carcin/bgv033

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Authors
Goodson, WH; Lowe, L; Carpenter, DO; Gilbertson, M; Manaf Ali, A; Lopez de Cerain Salsamendi, A; Lasfar, A; Carnero, A; Azqueta, A; Amedei, A; Charles, AK; Collins, AR; Ward, A; Salzberg, AC; Colacci, A; Olsen, A-K; Berg, A; Barclay, BJ; Zhou, BP; Blanco-Aparicio, C; Baglole, CJ; Dong, C; Mondello, C; Hsu, C-W; Naus, CC; Yedjou, C; Curran, CS; Laird, DW; Koch, DC; Carlin, DJ; Felsher, DW; Roy, D; Brown, DG; Ratovitski, E; Ryan, EP; Corsini, E; Rojas, E; Moon, E-Y; Laconi, E; Marongiu, F et al.
MLA Citation
Goodson, WH, Lowe, L, Carpenter, DO, Gilbertson, M, Manaf Ali, A, Lopez de Cerain Salsamendi, A, Lasfar, A, Carnero, A, Azqueta, A, Amedei, A, Charles, AK, Collins, AR, Ward, A, Salzberg, AC, Colacci, A, Olsen, A-K, Berg, A, Barclay, BJ, Zhou, BP, Blanco-Aparicio, C, Baglole, CJ, Dong, C, Mondello, C, Hsu, C-W, Naus, CC, Yedjou, C, Curran, CS, Laird, DW, Koch, DC, Carlin, DJ, Felsher, DW, Roy, D, Brown, DG, Ratovitski, E, Ryan, EP, Corsini, E, Rojas, E, Moon, E-Y, Laconi, E, and Marongiu, F et al. "Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead." Carcinogenesis 36 Suppl 1 (June 2015): S254-S296. (Review)
PMID
26106142
Source
epmc
Published In
Carcinogenesis
Volume
36 Suppl 1
Publish Date
2015
Start Page
S254
End Page
S296
DOI
10.1093/carcin/bgv039

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

Regional variation in identified cancer care needs of early-career oncologists in China, India, and Pakistan.

Cancer incidence and mortality is increasing in the developing world. Inequities between low-, middle-, and high-income countries affect disease burden and the infrastructure needs in response to cancer. We surveyed early-career oncologists attending workshops in clinical research in three countries with emerging economies about their perception of the evolving cancer burden.A cross-sectional survey questionnaire was distributed at clinical trial concept development workshops held in Beijing, Lahore, Karachi, and Mumbai at major hospitals to acquire information regarding home-country health conditions and needs.A total of 100 respondents participated in the workshops held at major hospitals in the region (India = 29, China = 25, Pakistan = 42, and other = 4). Expected consensus on many issues (e.g., emergence of cancer as a significant health issue) was balanced with significant variation in priorities, opportunities, and challenges. Chinese respondents prioritized improvements in cancer-specific care and palliative care, Indian respondents favored improved cancer detection and advancing research in cancer care, and Pakistani respondents prioritized awareness of cancer and improvements in disease detection and cancer care research. For all, the most frequently cited opportunity was help in improving professional cancer education and training.Predominantly early-career oncologists attending clinical research workshops (in China, India, and Pakistan) identified needs for increasing clinical cancer research, professional education, and public awareness of cancer. Decision makers supporting efforts to reduce the burden of cancer worldwide will need to factor the specific needs and aspirations of health care providers in their country in prioritizing health policies and budgets.

Authors
Lyerly, HK; Fawzy, MR; Aziz, Z; Nair, R; Pramesh, CS; Parmar, V; Parikh, PM; Jamal, R; Irumnaz, A; Ren, J; Stockler, MR; Abernethy, AP
MLA Citation
Lyerly, HK, Fawzy, MR, Aziz, Z, Nair, R, Pramesh, CS, Parmar, V, Parikh, PM, Jamal, R, Irumnaz, A, Ren, J, Stockler, MR, and Abernethy, AP. "Regional variation in identified cancer care needs of early-career oncologists in China, India, and Pakistan." The oncologist 20.5 (May 2015): 532-538.
PMID
25888267
Source
epmc
Published In
The oncologist
Volume
20
Issue
5
Publish Date
2015
Start Page
532
End Page
538
DOI
10.1634/theoncologist.2014-0213

Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis.

To evaluate the role of cardiovascular disease (CVD) comorbidity in survival of patients with non-small cell lung cancer (NSCLC).The impact of seven CVDs (at the time of NSCLC diagnosis and during subsequent follow-up) on overall survival was studied for NSCLC patients aged 65+ years using the Surveillance, Epidemiology, and End Results data linked to the U.S. Medicare data, cancer stage- and treatment-specific. Cox regression was applied to evaluate death hazard ratios of CVDs in univariable and multivariable analyses (controlling by age, TNM statuses, and 78 non-CVD comorbidities) and to investigate the effects of 128 different combinations of CVDs on patients' survival.Overall, 95,167 patients with stage I (n=29,836, 31.4%), II (n=5133, 5.4%), IIIA (n=11,884, 12.5%), IIIB (n=18,020, 18.9%), and IV (n=30,294, 31.8%) NSCLC were selected. Most CVDs increased the risk of death for stages I-IIIB patients, but did not significantly impact survival of stage IV patients. The worse survival of patients was associated with comorbid heart failure, myocardial infarction, and cardiac arrhythmias that occurred during a period of follow-up: HRs up to 1.85 (p<0.001), 1.96 (p<0.05), and 1.67 (p<0.001), respectively, varying by stage and treatment. The presence of hyperlipidemia at baseline (HR down to 0.71, p<0.05) was associated with better prognosis. Having multiple co-existing CVDs significantly increased mortality for all treatments, especially for stages I and II patients treated with surgery (HRs up to 2.89, p<0.05) and stages I-IIIB patients treated with chemotherapy (HRs up to 2.59, p<0.001) and chemotherapy and radiotherapy (HRs up to 2.20, p<0.001).CVDs impact the survival of NSCLC patients, particularly when multiple co-existing CVDs are present; the impacts vary by stage and treatment. This data should be considered in improving cancer treatment selection process for such potentially challenging patients as the elderly NSCLC patients with CVD comorbidities.

Authors
Kravchenko, J; Berry, M; Arbeev, K; Kim Lyerly, H; Yashin, A; Akushevich, I
MLA Citation
Kravchenko, J, Berry, M, Arbeev, K, Kim Lyerly, H, Yashin, A, and Akushevich, I. "Cardiovascular comorbidities and survival of lung cancer patients: Medicare data based analysis." Lung cancer (Amsterdam, Netherlands) 88.1 (April 2015): 85-93.
PMID
25704956
Source
epmc
Published In
Lung Cancer
Volume
88
Issue
1
Publish Date
2015
Start Page
85
End Page
93
DOI
10.1016/j.lungcan.2015.01.006

Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions.

Embryonic development and adult tissue homeostasis require precise information exchange between cells and their microenvironment to coordinate cell behavior. A specialized class of ultra-long actin-rich filopodia, termed cytonemes, provides one mechanism for this spatiotemporal regulation of extracellular cues. We provide here a mechanism whereby the stem-cell marker Lgr5, and its family member Lgr4, promote the formation of cytonemes. Lgr4- and Lgr5-induced cytonemes exceed lengths of 80 µm, are generated through stabilization of nascent filopodia from an underlying lamellipodial-like network and functionally provide a pipeline for the transit of signaling effectors. As proof-of-principle, we demonstrate that Lgr5-induced cytonemes act as conduits for cell signaling by demonstrating that the actin motor and filopodial cargo carrier protein myosin X (Myo10) and the G-protein-coupled receptor (GPCR) signaling effector β-arrestin-2 (Arrb2) transit into cytonemes. This work delineates a biological function for Lgr4 and Lgr5 and provides the rationale to fully investigate Lgr4 and Lgr5 function and cytonemes in mammalian stem cell and cancer stem cell behavior.

Authors
Snyder, JC; Rochelle, LK; Marion, S; Lyerly, HK; Barak, LS; Caron, MG
MLA Citation
Snyder, JC, Rochelle, LK, Marion, S, Lyerly, HK, Barak, LS, and Caron, MG. "Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions." Journal of cell science 128.6 (March 2015): 1230-1240.
PMID
25653388
Source
epmc
Published In
Journal of cell science
Volume
128
Issue
6
Publish Date
2015
Start Page
1230
End Page
1240
DOI
10.1242/jcs.166322

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

Continuous DC-CIK infusions restore CD8+ cellular immunity, physical activity and improve clinical efficacy in advanced cancer patients unresponsive to conventional treatments.

There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients.A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits.An average of 5.7±2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05).In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.

Authors
Zhao, Y-J; Jiang, N; Song, Q-K; Wu, J-P; Song, Y-G; Zhang, H-M; Chen, F; Zhou, L; Wang, X-L; Zhou, X-N; Yang, H-B; Ren, J; Lyerly, HK
MLA Citation
Zhao, Y-J, Jiang, N, Song, Q-K, Wu, J-P, Song, Y-G, Zhang, H-M, Chen, F, Zhou, L, Wang, X-L, Zhou, X-N, Yang, H-B, Ren, J, and Lyerly, HK. "Continuous DC-CIK infusions restore CD8+ cellular immunity, physical activity and improve clinical efficacy in advanced cancer patients unresponsive to conventional treatments." Asian Pacific journal of cancer prevention : APJCP 16.6 (January 2015): 2419-2423.
PMID
25824775
Source
epmc
Published In
Asian Pacific journal of cancer prevention : APJCP
Volume
16
Issue
6
Publish Date
2015
Start Page
2419
End Page
2423

Extracellular Hsp90 is actively trafficked and internalized in aggressive forms of breast cancer.

Authors
Burianek, LE; Hughes, PF; Osada, T; Alcorta, DA; Smith, AP; Spector, NL; Lyerly, HK; Haystead, TA
MLA Citation
Burianek, LE, Hughes, PF, Osada, T, Alcorta, DA, Smith, AP, Spector, NL, Lyerly, HK, and Haystead, TA. "Extracellular Hsp90 is actively trafficked and internalized in aggressive forms of breast cancer." 2015.
Source
wos-lite
Published In
Molecular Biology of the Cell
Volume
26
Publish Date
2015

N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization.

N-succinimidyl 4-guanidinomethyl-3-[(*)I]iodobenzoate ([(*)I]SGMIB) has shown promise for the radioiodination of monoclonal antibodies (mAbs) and other proteins that undergo extensive internalization after receptor binding, enhancing tumor targeting compared to direct electrophilic radioiodination. However, radiochemical yields for [(131)I]SGMIB synthesis are low, which we hypothesize is due to steric hindrance from the Boc-protected guanidinomethyl group ortho to the tin moiety. To overcome this, we developed the isomeric compound, N-succinimidyl 3-guanidinomethyl-5-[(131)I]iodobenzoate (iso-[(131)I]SGMIB) wherein this bulky group was moved from ortho to meta position.Boc2-iso-SGMIB standard and its tin precursor, N-succinimidyl 3-((1,2-bis(tert-butoxycarbonyl)guanidino)methyl)-5-(trimethylstannyl)benzoate (Boc2-iso-SGMTB), were synthesized using two disparate routes, and iso-[*I]SGMIB synthesized from the tin precursor. Two HER2-targeted vectors - trastuzumab (Tras) and a nanobody 5F7 (Nb) - were labeled using iso-[(*)I]SGMIB and [(*)I]SGMIB. Paired-label internalization assays in vitro with both proteins, and biodistribution in vivo with trastuzumab, labeled using the two isomeric prosthetic agents were performed.When the reactions were performed under identical conditions, radioiodination yields for the synthesis of Boc2-iso-[(131)I]SGMIB were significantly higher than those for Boc2-[(131)I]SGMIB (70.7±2.0% vs 56.5±5.5%). With both Nb and trastuzumab, conjugation efficiency also was higher with iso-[(131)I]SGMIB than with [(131)I]SGMIB (Nb, 33.1±7.1% vs 28.9±13.0%; Tras, 45.1±4.5% vs 34.8±10.3%); however, the differences were not statistically significant. Internalization assays performed on BT474 cells with 5F7 Nb indicated similar residualizing capacity over 6h; however, at 24h, radioactivity retained intracellularly for iso-[(131)I]SGMIB-Nb was lower than for [(125)I]SGMIB-Nb (46.4±1.3% vs 56.5±2.5%); similar results were obtained using Tras. Likewise, a paired-label biodistribution of Tras labeled using iso-[(125)I]SGMIB and [(131)I]SGMIB indicated an up to 22% tumor uptake advantage at later time points for [(131)I]SGMIB-Tras.Given the higher labeling efficiency obtained with iso-SGMIB, this residualizing agent might be of value for use with shorter half-life radiohalogens.

Authors
Choi, J; Vaidyanathan, G; Koumarianou, E; McDougald, D; Pruszynski, M; Osada, T; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Choi, J, Vaidyanathan, G, Koumarianou, E, McDougald, D, Pruszynski, M, Osada, T, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "N-Succinimidyl guanidinomethyl iodobenzoate protein radiohalogenation agents: influence of isomeric substitution on radiolabeling and target cell residualization." Nuclear medicine and biology 41.10 (November 2014): 802-812.
PMID
25156548
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
41
Issue
10
Publish Date
2014
Start Page
802
End Page
812
DOI
10.1016/j.nucmedbio.2014.07.005

A review of the health impacts of barium from natural and anthropogenic exposure.

There is an increasing public awareness of the relatively new and expanded industrial barium uses which are potential sources of human exposure (e.g., a shale gas development that causes an increased awareness of environmental exposures to barium). However, absorption of barium in exposed humans and a full spectrum of its health effects, especially among chronically exposed to moderate and low doses of barium populations, remain unclear. We suggest a systematic literature review (from 1875 to 2014) on environmental distribution of barium, its bioaccumulation, and potential and proven health impacts (in animal models and humans) to provide the information that can be used for optimization of future experimental and epidemiological studies and developing of mitigative and preventive strategies to minimize negative health effects in exposed populations. The potential health effects of barium exposure are largely based on animal studies, while epidemiological data for humans, specifically for chronic low-level exposures, are sparse. The reported health effects include cardiovascular and kidney diseases, metabolic, neurological, and mental disorders. Age, race, dietary patterns, behavioral risks (e.g., smoking), use of medications (those that interfere with absorbed barium in human organism), and specific physiological status (e.g., pregnancy) can modify barium effects on human health. Identifying, evaluating, and predicting the health effects of chronic low-level and moderate-level barium exposures in humans is challenging: Future research is needed to develop an understanding of barium bioaccumulation in order to mitigate its potential health impacts in various exposured populations. Further, while occupationally exposed at-risk populations exist, it is also important to identify potentially vulnerable subgroups among non-occupationally exposed populations (e.g., elderly, pregnant women, children) who are at higher risk of barium exposure from drinking water and food.

Authors
Kravchenko, J; Darrah, TH; Miller, RK; Lyerly, HK; Vengosh, A
MLA Citation
Kravchenko, J, Darrah, TH, Miller, RK, Lyerly, HK, and Vengosh, A. "A review of the health impacts of barium from natural and anthropogenic exposure." Environmental geochemistry and health 36.4 (August 2014): 797-814.
PMID
24844320
Source
epmc
Published In
Environmental Geochemistry and Health
Volume
36
Issue
4
Publish Date
2014
Start Page
797
End Page
814
DOI
10.1007/s10653-014-9622-7

A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype.

Despite improvements in adjuvant therapy, late systemic recurrences remain a lethal consequence of both early- and late-stage breast cancer. A delayed recurrence is thought to arise from a state of tumor dormancy, but the mechanisms that govern tumor dormancy remain poorly understood.To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. We interrogated the gene expression profiles of the 743 tumors and identified gene expression patterns that were associated with early and late disease recurrence among these patients. We applied this classification to a subset of 46 patients for whom expression data from microdissected tumor epithelium and stroma was available, and identified a distinct gene signature in the stroma and also a corresponding tumor epithelium signature that predicted disease recurrence in the discovery cohort. This tumor epithelium signature was then validated as a predictor for late disease recurrence in the entire cohort of 4,767 patients.We identified a novel 51-gene signature from microdissected tumor epithelium associated with late disease recurrence in breast cancer independent of the molecular disease subtype. This signature correlated with gene expression alterations in the adjacent tumor stroma and describes a process of epithelial to mesenchymal transition (EMT) and tumor-stroma interactions.Our findings suggest that an EMT-related gene signature in the tumor epithelium is related to both stromal activation and escape from disease dormancy in breast cancer. The presence of a late recurrence gene signature in the primary tumor also suggests that intrinsic features of this tumor regulate the transition of disseminated tumor cells into a dormant phenotype with the ability to outgrowth as recurrent disease.

Authors
Cheng, Q; Chang, JT; Gwin, WR; Zhu, J; Ambs, S; Geradts, J; Lyerly, HK
MLA Citation
Cheng, Q, Chang, JT, Gwin, WR, Zhu, J, Ambs, S, Geradts, J, and Lyerly, HK. "A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype." Breast cancer research : BCR 16.4 (July 25, 2014): 407-.
PMID
25060555
Source
epmc
Published In
Breast Cancer Research
Volume
16
Issue
4
Publish Date
2014
Start Page
407
DOI
10.1186/s13058-014-0407-9

Bisphenol a Interacts with Gper, Activates EGFR and ERK Signaling and Antagonizes Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Breast Cancer Cells

Authors
Sauer, SJ; Davis, JB; Lyerly, HK; Shah, I; Williams, KP; Devi, GR
MLA Citation
Sauer, SJ, Davis, JB, Lyerly, HK, Shah, I, Williams, KP, and Devi, GR. "Bisphenol a Interacts with Gper, Activates EGFR and ERK Signaling and Antagonizes Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Breast Cancer Cells." ENDOCRINE REVIEWS 35.3 (June 2014).
Source
wos-lite
Published In
Endocrine reviews
Volume
35
Issue
3
Publish Date
2014

Functional genomic screens and identification of signaling pathways in oxaliplatin-resistance in colorectal cancer.

Authors
Mettu, NB; Uronis, JM; Osada, T; Lu, M; Osada, K; Mook, R; Chen, W; Morse, M; Lyerly, HK; Wood, K; Hsu, SD
MLA Citation
Mettu, NB, Uronis, JM, Osada, T, Lu, M, Osada, K, Mook, R, Chen, W, Morse, M, Lyerly, HK, Wood, K, and Hsu, SD. "Functional genomic screens and identification of signaling pathways in oxaliplatin-resistance in colorectal cancer." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

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

Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis.

The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of human carcinoma cells.Brachyury mRNA and protein expression was analyzed in human breast carcinomas and benign tissues. The role of brachyury in breast tumor prognosis and drug resistance and the ability of brachyury-specific T cells to lyse human breast carcinoma cells were also evaluated. Kaplan-Meier analyses were used to evaluate the association between brachyury expression and survival. All statistical tests were two-sided.The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancer patients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence (hazard ratio [HR] = 7.5; 95% confidence interval [CI] = 2.4 to 23.5; P = 5.14×10(-4)) and distant metastasis (HR = 15.2; 95% CI = 3.5 to 66.3; P = 3.01×10(-4)). We also demonstrated that brachyury-specific T cells can lyse human breast carcinoma cells.The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies.

Authors
Palena, C; Roselli, M; Litzinger, MT; Ferroni, P; Costarelli, L; Spila, A; Cavaliere, F; Huang, B; Fernando, RI; Hamilton, DH; Jochems, C; Tsang, K-Y; Cheng, Q; Lyerly, HK; Schlom, J; Guadagni, F
MLA Citation
Palena, C, Roselli, M, Litzinger, MT, Ferroni, P, Costarelli, L, Spila, A, Cavaliere, F, Huang, B, Fernando, RI, Hamilton, DH, Jochems, C, Tsang, K-Y, Cheng, Q, Lyerly, HK, Schlom, J, and Guadagni, F. "Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis." Journal of the National Cancer Institute 106.5 (May 9, 2014).
PMID
24815864
Source
epmc
Published In
Journal of the National Cancer Institute
Volume
106
Issue
5
Publish Date
2014
DOI
10.1093/jnci/dju054

Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling.

Nanobodies are approximately 15-kDa proteins based on the smallest functional fragments of naturally occurring heavy chain-only antibodies and represent an attractive platform for the development of molecularly targeted agents for cancer diagnosis and therapy. Because the human epidermal growth factor receptor type 2 (HER2) is overexpressed in breast and ovarian carcinoma, as well as in other malignancies, HER2-specific Nanobodies may be valuable radiodiagnostics and therapeutics for these diseases. The aim of the present study was to evaluate the tumor-targeting potential of anti-HER2 5F7GGC Nanobody after radioiodination with the residualizing agent N-succinimidyl 4-guanidinomethyl 3-(125/131)I-iodobenzoate (*I-SGMIB).The 5F7GGC Nanobody was radiolabeled using *I-SGMIB and, for comparison, with N(ε)-(3-*I-iodobenzoyl)-Lys(5)-N(α)-maleimido-Gly(1)-GEEEK (*I-IB-Mal-d-GEEEK), another residualizing agent, and by direct radioiodination using IODO-GEN ((125)I-Nanobody). The 3 labeled Nanobodies were evaluated in affinity measurements, and paired-label internalization assays were performed on HER2-expressing BT474M1 breast carcinoma cells and in paired-label tissue distribution measurements in mice bearing subcutaneous BT474M1 xenografts.*I-SGMIB-Nanobody was produced in 50.4% ± 3.6% radiochemical yield and exhibited a dissociation constant of 1.5 ± 0.5 nM. Internalization assays demonstrated that intracellular retention of radioactivity was up to 1.5-fold higher for *I-SGMIB-Nanobody than for coincubated (125)I-Nanobody or *I-IB-Mal-d-GEEEK-Nanobody. Peak tumor uptake for *I-SGMIB-Nanobody was 24.50% ± 9.89% injected dose/g at 2 h, 2- to 4-fold higher than observed with other labeling methods, and was reduced by 90% with trastuzumab blocking, confirming the HER2 specificity of localization. Moreover, normal-organ clearance was fastest for *I-SGMIB-Nanobody, such that tumor-to-normal-organ ratios greater than 50:1 were reached by 24 h in all tissues except lungs and kidneys, for which the values were 10.4 ± 4.5 and 5.2 ± 1.5, respectively.Labeling anti-HER2 Nanobody 5F7GGC with *I-SGMIB yields a promising new conjugate for targeting HER2-expressing malignancies. Further research is needed to determine the potential utility of *I-SGMIB-5F7GGC labeled with (124)I, (123)I, and (131)I for PET and SPECT imaging and for targeted radiotherapy, respectively.

Authors
Pruszynski, M; Koumarianou, E; Vaidyanathan, G; Revets, H; Devoogdt, N; Lahoutte, T; Lyerly, HK; Zalutsky, MR
MLA Citation
Pruszynski, M, Koumarianou, E, Vaidyanathan, G, Revets, H, Devoogdt, N, Lahoutte, T, Lyerly, HK, and Zalutsky, MR. "Improved tumor targeting of anti-HER2 nanobody through N-succinimidyl 4-guanidinomethyl-3-iodobenzoate radiolabeling." Journal of nuclear medicine : official publication, Society of Nuclear Medicine 55.4 (April 2014): 650-656.
PMID
24578241
Source
epmc
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
55
Issue
4
Publish Date
2014
Start Page
650
End Page
656
DOI
10.2967/jnumed.113.127100

A review of the health impacts of barium from natural and anthropogenic exposure

There is an increasing public awareness of the relatively new and expanded industrial barium uses which are potential sources of human exposure (e.g., a shale gas development that causes an increased awareness of environmental exposures to barium). However, absorption of barium in exposed humans and a full spectrum of its health effects, especially among chronically exposed to moderate and low doses of barium populations, remain unclear. We suggest a systematic literature review (from 1875 to 2014) on environmental distribution of barium, its bioaccumulation, and potential and proven health impacts (in animal models and humans) to provide the information that can be used for optimization of future experimental and epidemiological studies and developing of mitigative and preventive strategies to minimize negative health effects in exposed populations. The potential health effects of barium exposure are largely based on animal studies, while epidemiological data for humans, specifically for chronic low-level exposures, are sparse. The reported health effects include cardiovascular and kidney diseases, metabolic, neurological, and mental disorders. Age, race, dietary patterns, behavioral risks (e.g., smoking), use of medications (those that interfere with absorbed barium in human organism), and specific physiological status (e.g., pregnancy) can modify barium effects on human health. Identifying, evaluating, and predicting the health effects of chronic low-level and moderate-level barium exposures in humans is challenging: Future research is needed to develop an understanding of barium bioaccumulation in order to mitigate its potential health impacts in various exposured populations. Further, while occupationally exposed at-risk populations exist, it is also important to identify potentially vulnerable subgroups among non-occupationally exposed populations (e.g., elderly, pregnant women, children) who are at higher risk of barium exposure from drinking water and food. © 2014 Springer Science+Business Media Dordrecht.

Authors
Kravchenko, J; Darrah, TH; Miller, RK; Lyerly, HK; Vengosh, A
MLA Citation
Kravchenko, J, Darrah, TH, Miller, RK, Lyerly, HK, and Vengosh, A. "A review of the health impacts of barium from natural and anthropogenic exposure." Environmental Geochemistry and Health 36.4 (January 1, 2014): 797-814.
Source
scopus
Published In
Environmental Geochemistry and Health
Volume
36
Issue
4
Publish Date
2014
Start Page
797
End Page
814
DOI
10.1007/s10653-014-9622-7

Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis.

The epithelial-mesenchymal transition (EMT) has been implicated as an important process in tumor cell invasion, metastasis, and drug resistance. The transcription factor brachyury has recently been described as a driver of EMT of human carcinoma cells. Brachyury mRNA and protein expression was analyzed in human breast carcinomas and benign tissues. The role of brachyury in breast tumor prognosis and drug resistance and the ability of brachyury-specific T cells to lyse human breast carcinoma cells were also evaluated. Kaplan-Meier analyses were used to evaluate the association between brachyury expression and survival. All statistical tests were two-sided. The level of brachyury expression in breast cancer cells was positively associated with their ability to invade the extracellular matrix, efficiently form mammospheres in vitro, and resist the cytotoxic effect of docetaxel. A comparison of survival among breast cancer patients treated with tamoxifen in the adjuvant setting who had tumors with high vs low brachyury mRNA expression demonstrated that high expression of brachyury is associated as an independent variable with higher risk of recurrence (hazard ratio [HR] = 7.5; 95% confidence interval [CI] = 2.4 to 23.5; P = 5.14×10(-4)) and distant metastasis (HR = 15.2; 95% CI = 3.5 to 66.3; P = 3.01×10(-4)). We also demonstrated that brachyury-specific T cells can lyse human breast carcinoma cells. The studies reported here provide the rationale for the use of a vaccine targeting brachyury for the therapy of human breast cancer, either as a monotherapy or in combination therapies. Published by Oxford University Press 2014.

Authors
Palena, C; Roselli, M; Litzinger, MT; Ferroni, P; Costarelli, L; Spila, A; Cavaliere, F; Huang, B; Fernando, RI; Hamilton, DH; Jochems, C; Tsang, KY; Cheng, Q; Kim Lyerly, H; Schlom, J; Guadagni, F
MLA Citation
Palena, C, Roselli, M, Litzinger, MT, Ferroni, P, Costarelli, L, Spila, A, Cavaliere, F, Huang, B, Fernando, RI, Hamilton, DH, Jochems, C, Tsang, KY, Cheng, Q, Kim Lyerly, H, Schlom, J, and Guadagni, F. "Overexpression of the EMT driver brachyury in breast carcinomas: association with poor prognosis." Journal of the National Cancer Institute 106.5 (January 1, 2014).
Source
scopus
Published In
Journal of the National Cancer Institute
Volume
106
Issue
5
Publish Date
2014

Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality.

BACKGROUND: The respiratory tract is a major target of exposure to air pollutants, and respiratory diseases are associated with both short- and long-term exposures. We hypothesized that improved air quality in North Carolina was associated with reduced rates of death from respiratory diseases in local populations. MATERIALS AND METHODS: We analyzed the trends of emphysema, asthma, and pneumonia mortality and changes of the levels of ozone, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and particulate matters (PM2.5 and PM10) using monthly data measurements from air-monitoring stations in North Carolina in 1993-2010. The log-linear model was used to evaluate associations between air-pollutant levels and age-adjusted death rates (per 100,000 of population) calculated for 5-year age-groups and for standard 2000 North Carolina population. The studied associations were adjusted by age group-specific smoking prevalence and seasonal fluctuations of disease-specific respiratory deaths. RESULTS: Decline in emphysema deaths was associated with decreasing levels of SO2 and CO in the air, decline in asthma deaths-with lower SO2, CO, and PM10 levels, and decline in pneumonia deaths-with lower levels of SO2. Sensitivity analyses were performed to study potential effects of the change from International Classification of Diseases (ICD)-9 to ICD-10 codes, the effects of air pollutants on mortality during summer and winter, the impact of approach when only the underlying causes of deaths were used, and when mortality and air-quality data were analyzed on the county level. In each case, the results of sensitivity analyses demonstrated stability. The importance of analysis of pneumonia as an underlying cause of death was also highlighted. CONCLUSION: Significant associations were observed between decreasing death rates of emphysema, asthma, and pneumonia and decreases in levels of ambient air pollutants in North Carolina.

Authors
Kravchenko, J; Akushevich, I; Abernethy, AP; Holman, S; Ross, WG; Lyerly, HK
MLA Citation
Kravchenko, J, Akushevich, I, Abernethy, AP, Holman, S, Ross, WG, and Lyerly, HK. "Long-term dynamics of death rates of emphysema, asthma, and pneumonia and improving air quality." International journal of chronic obstructive pulmonary disease 9 (January 2014): 613-627.
Website
http://hdl.handle.net/10161/8919
PMID
25018627
Source
epmc
Published In
International journal of chronic obstructive pulmonary disease
Volume
9
Publish Date
2014
Start Page
613
End Page
627
DOI
10.2147/copd.s59995

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

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

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

BACKGROUND: We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. CONCLUSION: Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Authors
Ren, J; Di, L; Song, G; Yu, J; Jia, J; Zhu, Y; Yan, Y; Jiang, H; Liang, X; Che, L; Zhang, J; Wan, F; Wang, X; Zhou, X; Lyerly, HK
MLA Citation
Ren, J, Di, L, Song, G, Yu, J, Jia, J, Zhu, Y, Yan, Y, Jiang, H, Liang, X, Che, L, Zhang, J, Wan, F, Wang, X, Zhou, X, and Lyerly, HK. "Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences." Clin Transl Oncol 15.10 (October 2013): 780-788.
PMID
23359185
Source
pubmed
Published In
Clinical and Translational Oncology
Volume
15
Issue
10
Publish Date
2013
Start Page
780
End Page
788
DOI
10.1007/s12094-013-1001-9

Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethyleneglycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging.

Authors
Barrott, JJ; Hughes, PF; Osada, T; Yang, X-Y; Hartman, ZC; Loiselle, DR; Spector, NL; Neckers, L; Rajaram, N; Hu, F; Ramanujam, N; Vaidyanathan, G; Zalutsky, MR; Lyerly, HK; Haystead, TA
MLA Citation
Barrott, JJ, Hughes, PF, Osada, T, Yang, X-Y, Hartman, ZC, Loiselle, DR, Spector, NL, Neckers, L, Rajaram, N, Hu, F, Ramanujam, N, Vaidyanathan, G, Zalutsky, MR, Lyerly, HK, and Haystead, TA. "Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells." Chem Biol 20.9 (September 19, 2013): 1187-1197.
PMID
24035283
Source
pubmed
Published In
Chemistry and Biology
Volume
20
Issue
9
Publish Date
2013
Start Page
1187
End Page
1197
DOI
10.1016/j.chembiol.2013.08.004

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

Bridging the information gap between health and the environment in North Carolina.

OBJECTIVE: To better understand relationships between health and environmental hazards in North Carolina, a transdisciplinary group of participants from government and nongovernmental organizations (NFPs and universities) were appointed by the Research Triangle Environmental Health Collaborative to identify databases that when linked could lead toward improved environmental public health surveillance. DESIGN: The workgroup identified and compiled a comprehensive data resource directory containing information on 74 key health and environmental databases. Previous examples of data linkage projects in North Carolina using data sets were demonstrated. RESULTS: A single, high-quality directory of existing databases on health and the environment is now readily available. Data sets have independent values; when combined, these could prove increasingly important to evaluate health associations, particularly for researchers and policy makers. CONCLUSION: A pilot study to further demonstrate the importance of using the Environmental Health Database Inventory as a reference for data linkage projects is highly warranted.

Authors
Kearney, GD; Shehee, M; Lyerly, HK
MLA Citation
Kearney, GD, Shehee, M, and Lyerly, HK. "Bridging the information gap between health and the environment in North Carolina." J Public Health Manag Pract 19.5 (September 2013): 475-478.
PMID
23896978
Source
pubmed
Published In
Journal of Public Health Management and Practice
Volume
19
Issue
5
Publish Date
2013
Start Page
475
End Page
478
DOI
10.1097/PHH.0b013e318280010e

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

Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy.

PURPOSE: Suppression of cellular immunity resulting from tumorigenesis and/or therapy might promote cancer cells' growth, progression and invasion. Here, we explored whether T lymphocyte subtypes from peripheral blood of metastatic breast cancer (MBC) female patients could be used as alternative surrogate markers for cancer progress. Additionally, plasma levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, and transforming growth factor-β1 were quantitated from MBC and healthy volunteers. EXPERIMENTAL DESIGN: This study included 89 female MBC patients during the post-salvage chemotherapy follow-up and 50 age- and sex-matched healthy volunteers as control. The percentages of T lymphocyte subpopulations from peripheral blood and plasma levels of cytokines were measured. RESULTS: Both CD8(+)CD28(-) and CD4(+)CD25(+) were elevated in MBC patients compared to the control cohort (P < 0.05). In contrast, CD3(+) and CD8(+)CD28(+)cells were significantly lower in MBC patients (P < 0.0001, P = 0.045, respectively). MBC patients had elevated levels of immunosuppressive cytokines IL-6 and IL-10. Patients with elevated CD8(+)CD28(-) and CD4(+)CD25(+) cells showed increased levels of IL-6, and only patients with elevated CD8(+)CD28(-) had decreased interferon-γ. Univariate analysis indicated increased CD3(+)CD4(+) or CD8(+)CD28(+)correlated with prolonged progression-free survival (PFS), while elevated CD8(+)CD28(-)associated with shorten PFS. The percent of CD8(+)CD28(-) T lymphocytes is an independent predictor for PFS through multivariate analysis. CONCLUSIONS: This study suggests that progressive elevated levels of CD8(+)CD28(-) suppressor T lymphocytes represent a novel independent predictor of PFS during post-chemotherapy follow-up.

Authors
Song, G; Wang, X; Jia, J; Yuan, Y; Wan, F; Zhou, X; Yang, H; Ren, J; Gu, J; Lyerly, HK
MLA Citation
Song, G, Wang, X, Jia, J, Yuan, Y, Wan, F, Zhou, X, Yang, H, Ren, J, Gu, J, and Lyerly, HK. "Elevated level of peripheral CD8(+)CD28(-) T lymphocytes are an independent predictor of progression-free survival in patients with metastatic breast cancer during the course of chemotherapy." Cancer Immunol Immunother 62.6 (June 2013): 1123-1130.
PMID
23604172
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
1123
End Page
1130
DOI
10.1007/s00262-013-1424-8

Abstract 5681: Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives.

Authors
Mook, RA; Chen, M; Lu, J; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Mook, RA, Chen, M, Lu, J, Barak, LS, Lyerly, HK, and Chen, W. "Abstract 5681: Modulation of Wnt/β-catenin signaling by niclosamide and related derivatives." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
5681
End Page
5681
DOI
10.1158/1538-7445.AM2013-5681

Abstract 5298: Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients.

Authors
Yu, J; Dong, N; Yan, Y; Shao, B; Di, L; Song, G; Che, L; Jia, J; Jiang, H; Liang, X; Zhu, Y; Wang, C; Zahng, J; Zhu, B; Zhou, X; Wang, X; Yang, H; Ren, J; Lyerly, HK
MLA Citation
Yu, J, Dong, N, Yan, Y, Shao, B, Di, L, Song, G, Che, L, Jia, J, Jiang, H, Liang, X, Zhu, Y, Wang, C, Zahng, J, Zhu, B, Zhou, X, Wang, X, Yang, H, Ren, J, and Lyerly, HK. "Abstract 5298: Two distinctive single nucleotide polymorphisms determine liver metastases responses to docetaxel plus thiotepa for metastatic breast cancer patients." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
5298
End Page
5298
DOI
10.1158/1538-7445.AM2013-5298

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

Small molecule modulators of Wnt/β-catenin signaling.

The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling by a unique mechanism, though the target responsible remains unknown. We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts. We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide. Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/β-catenin signaling and the discovery of potent and selective modulators to treat human disease.

Authors
Mook, RA; Chen, M; Lu, J; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Mook, RA, Chen, M, Lu, J, Barak, LS, Lyerly, HK, and Chen, W. "Small molecule modulators of Wnt/β-catenin signaling." Bioorg Med Chem Lett 23.7 (April 1, 2013): 2187-2191.
PMID
23453073
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry Letters
Volume
23
Issue
7
Publish Date
2013
Start Page
2187
End Page
2191
DOI
10.1016/j.bmcl.2013.01.101

Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network.

LGR5 is a Wnt pathway associated G protein-coupled receptor (GPCR) that serves as a molecular determinant of stem cells in numerous tissues including the intestine, stomach, hair follicle, eye, and mammary gland. Despite its importance as a marker for this critical niche, little is known about LGR5 signaling nor the biochemical mechanisms and receptor determinants that regulate LGR5 membrane expression and intracellular trafficking. Most importantly, in cells LGR5 is predominantly intracellular, yet the mechanisms underlying this behavior have not been determined. In this work we elucidate a precise trafficking program for LGR5 and identify the motif at its C terminus that is responsible for the observed constitutive internalization. We show that this process is dependent upon dynamin GTPase activity and find that wild-type full-length LGR5 rapidly internalizes into EEA1- and Rab5-positive endosomes. However, LGR5 fails to rapidly recycle to the plasmid membrane through Rab4-positive vesicles, as is common for other GPCRs. Rather, internalized LGR5 transits through Rab7- and Rab9-positive vesicles, co-localizes in vesicles with Vps26, a retromer complex component that regulates retrograde trafficking to the trans-Golgi network (TGN) and reaches a steady-state distribution in the TGN within 2 h. Using mutagenesis, particularly of putative phosphorylation sites, we show that the amino acid pair, serine 861 and 864, is the principal C-tail determinant that mediates LGR5 constitutive internalization. The constitutive internalization of LGR5 to the TGN suggests the existence of novel biochemical roles for its Wnt pathway related, but ill defined signaling program.

Authors
Snyder, JC; Rochelle, LK; Lyerly, HK; Caron, MG; Barak, LS
MLA Citation
Snyder, JC, Rochelle, LK, Lyerly, HK, Caron, MG, and Barak, LS. "Constitutive internalization of the leucine-rich G protein-coupled receptor-5 (LGR5) to the trans-Golgi network." The Journal of biological chemistry 288.15 (April 2013): 10286-10297.
PMID
23439653
Source
epmc
Published In
The Journal of biological chemistry
Volume
288
Issue
15
Publish Date
2013
Start Page
10286
End Page
10297
DOI
10.1074/jbc.m112.447540

DEVELOPMENT OF A NOVEL SMALL MOLECULE INHIBITOR OF SMOOTHENED FOR MEDULLOBLASTOMA TREATMENT

Authors
Chen, M; Lu, J; Wang, J; Keir, S; Zhang, M; Zhao, S; Mook, R; Barak, L; Lyerly, HK; Chen, W
MLA Citation
Chen, M, Lu, J, Wang, J, Keir, S, Zhang, M, Zhao, S, Mook, R, Barak, L, Lyerly, HK, and Chen, W. "DEVELOPMENT OF A NOVEL SMALL MOLECULE INHIBITOR OF SMOOTHENED FOR MEDULLOBLASTOMA TREATMENT." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
7
End Page
8

Minimization of heatwave morbidity and mortality.

Global climate change is projected to increase the frequency and duration of periods of extremely high temperatures. Both the general populace and public health authorities often underestimate the impact of high temperatures on human health. To highlight the vulnerable populations and illustrate approaches to minimization of health impacts of extreme heat, the authors reviewed the studies of heat-related morbidity and mortality for high-risk populations in the U.S. and Europe from 1958 to 2012. Heat exposure not only can cause heat exhaustion and heat stroke but also can exacerbate a wide range of medical conditions. Vulnerable populations, such as older adults; children; outdoor laborers; some racial and ethnic subgroups (particularly those with low SES); people with chronic diseases; and those who are socially or geographically isolated, have increased morbidity and mortality during extreme heat. In addition to ambient temperature, heat-related health hazards are exacerbated by air pollution, high humidity, and lack of air-conditioning. Consequently, a comprehensive approach to minimize the health effects of extreme heat is required and must address educating the public of the risks and optimizing heatwave response plans, which include improving access to environmentally controlled public havens, adaptation of social services to address the challenges required during extreme heat, and consistent monitoring of morbidity and mortality during periods of extreme temperatures.

Authors
Kravchenko, J; Abernethy, AP; Fawzy, M; Lyerly, HK
MLA Citation
Kravchenko, J, Abernethy, AP, Fawzy, M, and Lyerly, HK. "Minimization of heatwave morbidity and mortality." American journal of preventive medicine 44.3 (March 2013): 274-282.
PMID
23415125
Source
epmc
Published In
American Journal of Preventive Medicine
Volume
44
Issue
3
Publish Date
2013
Start Page
274
End Page
282
DOI
10.1016/j.amepre.2012.11.015

A molecular profile of colorectal cancer to guide prognosis and therapy after resection of primary or metastatic disease

Authors
Uronis, JM; VanDeusen, JB; Datto, MB; Lucas, J; Morse, M; Mantyh, C; Lyerly, HK; Clary, BM; Hsu, SD
MLA Citation
Uronis, JM, VanDeusen, JB, Datto, MB, Lucas, J, Morse, M, Mantyh, C, Lyerly, HK, Clary, BM, and Hsu, SD. "A molecular profile of colorectal cancer to guide prognosis and therapy after resection of primary or metastatic disease." February 1, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
4
Publish Date
2013

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

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

Regulation of hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1.

Smoothened (Smo) mediated Hedgehog (Hh) signaling plays an essential role in regulating embryonic development and postnatal tissue homeostasis. Aberrant activation of the Hh pathway contributes to the formation and progression of various cancers. In vertebrates, however, key regulatory mechanisms responsible for transducing signals from Smo to the nucleus remain to be delineated. Here, we report the identification of Myc-interacting Zinc finger protein 1 (Miz1) as a Smo and Gli2 binding protein that positively regulates Hh signaling. Overexpression of Miz1 increases Gli luciferase reporter activity, whereas knockdown of endogenous Miz1 has the opposite effect. Activation of Smo induces translocation of Miz1 to the primary cilia together with Smo and Gli2. Furthermore, Miz1 is localized to the nucleus upon Hh activation in a Smo-dependent manner, and loss of Miz1 prevents the nuclear translocation of Gli2. More importantly, silencing Miz1 expression inhibits cell proliferation in vitro and the growth of Hh-driven medulloblastoma tumors allografted in SCID mice. Taken together, these results identify Miz1 as a novel regulator in the Hh pathway that plays an important role in mediating Smo-dependent oncogenic signaling.

Authors
Lu, J; Chen, M; Ren, X-R; Wang, J; Lyerly, HK; Barak, L; Chen, W
MLA Citation
Lu, J, Chen, M, Ren, X-R, Wang, J, Lyerly, HK, Barak, L, and Chen, W. "Regulation of hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1. (Published online)" PLoS One 8.5 (2013): e63353-.
PMID
23671675
Source
pubmed
Published In
PloS one
Volume
8
Issue
5
Publish Date
2013
Start Page
e63353
DOI
10.1371/journal.pone.0063353

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

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

An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models.

INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase (RTK) oncogene is an attractive therapeutic target for the treatment of HER2-addicted tumors. Although lapatinib, an FDA-approved small-molecule HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), represents a significant therapeutic advancement in the treatment of HER2+ breast cancers, responses to lapatinib have not been durable. Consequently, elucidation of mechanisms of acquired therapeutic resistance to HER-directed therapies is of critical importance. METHODS: Using a functional protein-pathway activation mapping strategy, along with targeted genomic knockdowns applied to a series of isogenic-matched pairs of lapatinib-sensitive and resistant cell lines, we now report an unexpected mechanism of acquired resistance to lapatinib and similar TKIs. RESULTS: The signaling analysis revealed that whereas HER2 was appropriately inhibited in lapatinib-resistant cells, EGFR tyrosine phosphorylation was incompletely inhibited. Using a targeted molecular knockdown approach to interrogate the causal molecular underpinnings of EGFR-persistent activation, we found that lapatinib-resistant cells were no longer oncogene addicted to HER2-HER3-PI3K signaling, as seen in the parental lapatinib-sensitive cell lines, but instead were dependent on a heregulin (HRG)-driven HER3-EGFR-PI3K-PDK1 signaling axis. Two FDA-approved EGFR TKIs could not overcome HRG-HER3-mediated activation of EGFR, or reverse lapatinib resistance. The ability to overcome EGFR-mediated acquired therapeutic resistance to lapatinib was demonstrated through molecular knockdown of EGFR and treatment with the irreversible pan-HER TKI neratinib, which blocked HRG-dependent phosphorylation of HER3 and EGFR, resulting in apoptosis of resistant cells. In addition, whereas HRG reversed lapatinib-mediated antitumor effects in parental HER2+ breast cancer cells, neratinib was comparatively resistant to the effects of HRG in parental cells. Finally, we showed that HRG expression is an independent negative predictor of clinical outcome in HER2+ breast cancers, providing potential clinical relevance to our findings. CONCLUSIONS: Molecular analysis of acquired therapeutic resistance to lapatinib identified a new resistance mechanism based on incomplete and "leaky" inhibition of EGFR by lapatinib. The selective pressure applied by incomplete inhibition of the EGFR drug target resulted in selection of ligand-driven feedback that sustained EGFR activation in the face of constant exposure to the drug. Inadequate target inhibition driven by a ligand-mediated autocrine feedback loop may represent a broader mechanism of therapeutic resistance to HER TKIs and suggests adopting a different strategy for selecting more effective TKIs to advance into the clinic.

Authors
Xia, W; Petricoin, EF; Zhao, S; Liu, L; Osada, T; Cheng, Q; Wulfkuhle, JD; Gwin, WR; Yang, X; Gallagher, RI; Bacus, S; Lyerly, HK; Spector, NL
MLA Citation
Xia, W, Petricoin, EF, Zhao, S, Liu, L, Osada, T, Cheng, Q, Wulfkuhle, JD, Gwin, WR, Yang, X, Gallagher, RI, Bacus, S, Lyerly, HK, and Spector, NL. "An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models." Breast Cancer Res 15.5 (2013): R85-.
PMID
24044505
Source
pubmed
Published In
Breast Cancer Research
Volume
15
Issue
5
Publish Date
2013
Start Page
R85
DOI
10.1186/bcr3480

Abstract P4-08-07: Novel insight into the tumor “flare” phenomenon and lapatinib resistance

Authors
Piede, JA; Zhao, S; Liu, L; Lyerly, HK; Osada, T; Wang, T; Xia, W; Spector, N
MLA Citation
Piede, JA, Zhao, S, Liu, L, Lyerly, HK, Osada, T, Wang, T, Xia, W, and Spector, N. "Abstract P4-08-07: Novel insight into the tumor “flare” phenomenon and lapatinib resistance." Cancer Research 72.24 Supplement (December 15, 2012): P4-08-07-P4-08-07.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
24 Supplement
Publish Date
2012
Start Page
P4-08-07
End Page
P4-08-07
DOI
10.1158/0008-5472.SABCS12-P4-08-07

Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling.

The Hedgehog signaling pathway plays an essential role in embryo development and adult tissue homeostasis, in regulating stem cells and is abnormally activated in many cancers. Given the importance of this signaling pathway, we developed a novel and versatile high-throughput, cell-based screening platform using confocal imaging, based on the role of β-arrestin in Hedgehog signal transduction, that can identify agonists or antagonist of the pathway by a simple change to the screening protocol. Here we report the use of this assay in the antagonist mode to identify novel antagonists of Smoothened, including a compound (A8) with low nanomolar activity against wild-type Smo also capable of binding the Smo point mutant D473H associated with clinical resistance in medulloblastoma. Our data validate this novel screening approach in the further development of A8 and related congeners to treat Hedgehog related diseases, including the treatment of basal cell carcinoma and medulloblastoma.

Authors
Wang, J; Mook, RA; Lu, J; Gooden, DM; Ribeiro, A; Guo, A; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Wang, J, Mook, RA, Lu, J, Gooden, DM, Ribeiro, A, Guo, A, Barak, LS, Lyerly, HK, and Chen, W. "Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling." Bioorg Med Chem 20.22 (November 15, 2012): 6751-6757.
PMID
23063522
Source
pubmed
Published In
Bioorganic & Medicinal Chemistry
Volume
20
Issue
22
Publish Date
2012
Start Page
6751
End Page
6757
DOI
10.1016/j.bmc.2012.09.030

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

Smac Mimetic Induces Apoptosis and Synergizes with TRAIL in Inflammatory Breast Cancer Cells in an IAP-Dependent and TNF-a-Independent Mechanism

Authors
Devi, GR; Allensworth, JL; Sauer, SJ; Morse, MM; Lyerly, HK
MLA Citation
Devi, GR, Allensworth, JL, Sauer, SJ, Morse, MM, and Lyerly, HK. "Smac Mimetic Induces Apoptosis and Synergizes with TRAIL in Inflammatory Breast Cancer Cells in an IAP-Dependent and TNF-a-Independent Mechanism." November 2012.
Source
wos-lite
Published In
European Journal of Cancer
Volume
48
Publish Date
2012
Start Page
32
End Page
32

Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector

Authors
Gabitzsch, ES; Morse, M; Hobeika, A; Xu, Y; Balint, J; Balcaitis, S; Lyerly, HK; Jones, FR
MLA Citation
Gabitzsch, ES, Morse, M, Hobeika, A, Xu, Y, Balint, J, Balcaitis, S, Lyerly, HK, and Jones, FR. "Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector." October 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
30
Publish Date
2012

Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector.

85 Background: The major limitation for the use of Ad5 and other vectored vaccines is the inability to be effective in the presence of pre-existing or concomitant vector immunity. An Ad5-based vector with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), by virtue of diminished late phase viral protein expression, avoids immunological clearance and induces immune responses.The Ad5 [E1-, E2b-] platform encoding tumor associated antigen(s) (TAA) such as a modified carcinoembryonic antigen (CEA(6D)), HER2 and HPV E6/E7, were evaluated for the induction of TAA specific immune responses and anti-tumor effects in murine models. In a phase I/II clinical trial, cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2b-]-CEA(6D) (10(9) to 10(11) vp) subcutaneously every 3 weeks for 3 immunizations. CEA-specific cell mediated immunity was measured by ELISPOT.In murine immunotherapy studies, mice implanted with tumors expressing TAA and subsequently treated with the Ad5 [E1-, E2b-] platform expressing that TAA had significant inhibition of tumor progression. Pre-vaccination against the TAA utilizing the Ad5 [E1-, E2b-]-TAA resulted in inhibition of tumor establishment. In a clinical trial, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities.The results demonstrate that the novel Ad5 [E1-, E2b-] gene delivery platform can both break tolerance and generate significant CMI responses to the TAA CEA in the setting of both naturally acquired Ad5-specific immunity and/or immunization-induced Ad5 immunity.

Authors
Morse, M; Hobeika, A; Xu, Y; Balint, J; Balcaitis, S; Lyerly, HK; Jones, FR
MLA Citation
Morse, M, Hobeika, A, Xu, Y, Balint, J, Balcaitis, S, Lyerly, HK, and Jones, FR. "Ad5 immunity after multiple safe, homologous immunizations against tumor-associated antigens with new recombinant Ad5 vector." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.30_suppl (October 2012): 85-.
PMID
28142493
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
30_suppl
Publish Date
2012
Start Page
85

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

The insecticide synergist piperonyl butoxide inhibits hedgehog signaling: assessing chemical risks.

The spread of chemicals, including insecticides, into the environment often raises public health concerns, as exemplified by a recent epidemiologic study associating in utero piperonyl butoxide (PBO) exposure with delayed mental development. The insecticide synergist PBO is listed among the top 10 chemicals detected in indoor dust; a systematic assessment of risks from PBO exposure, as for many toxicants unfortunately, may be underdeveloped when important biological targets that can cause toxicity are unknown. Hedgehog/Smoothened signaling is critical in neurological development. This study was designed to use novel high-throughput in vitro drug screening technology to identify modulators of Hedgehog signaling in environmental chemicals to assist the assessment of their potential risks. A directed library of 1408 environmental toxicants was screened for Hedgehog/Smoothened antagonist activity using a high-content assay that evaluated the interaction between Smoothened and βarrestin2 green fluorescent protein. PBO was identified as a Hedgehog/Smoothened antagonist capable of inhibiting Hedgehog signaling. We found that PBO bound Smoothened and blocked Smoothened overexpression-induced Gli-luciferase reporter activity but had no effect on Gli-1 downstream transcriptional factor-induced Gli activity. PBO inhibited Sonic Hedgehog ligand-induced Gli signaling and mouse cerebellar granular precursor cell proliferation. Moreover, PBO disrupted zebrafish development. Our findings demonstrate the value of high-throughput target-based screening strategies that can successfully evaluate large numbers of environmental toxicants and identify key targets and unknown biological activity that is helpful in properly assessing potential risks.

Authors
Wang, J; Lu, J; Mook, RA; Zhang, M; Zhao, S; Barak, LS; Freedman, JH; Lyerly, HK; Chen, W
MLA Citation
Wang, J, Lu, J, Mook, RA, Zhang, M, Zhao, S, Barak, LS, Freedman, JH, Lyerly, HK, and Chen, W. "The insecticide synergist piperonyl butoxide inhibits hedgehog signaling: assessing chemical risks." Toxicol Sci 128.2 (August 2012): 517-523.
PMID
22552772
Source
pubmed
Published In
Toxicological Sciences (Elsevier)
Volume
128
Issue
2
Publish Date
2012
Start Page
517
End Page
523
DOI
10.1093/toxsci/kfs165

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

Effect of the loss of the type III TGF beta receptor during tumor progression on tumor microenvironment: Preclinical development of TGF beta inhibition and TGF beta-related biomarkers to enhance immunotherapy efficacy.

Authors
Hanks, BA; Holtzhausen, A; Gimpel, P; Jamieson, R; Campbell, OM; Sun, L; Augustine, CK; Tyler, DS; Osada, T; Morse, M; Ling, LE; Lyerly, HK; Blobe, GC
MLA Citation
Hanks, BA, Holtzhausen, A, Gimpel, P, Jamieson, R, Campbell, OM, Sun, L, Augustine, CK, Tyler, DS, Osada, T, Morse, M, Ling, LE, Lyerly, HK, and Blobe, GC. "Effect of the loss of the type III TGF beta receptor during tumor progression on tumor microenvironment: Preclinical development of TGF beta inhibition and TGF beta-related biomarkers to enhance immunotherapy efficacy." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial

Authors
Morse, M; Hobeika, A; Chaudhry, A; Amalfitano, A; Niedzwiecki, D; Clay, TM; Osada, T; Devi, G; Burnett, BK; Weinhold, K; Hsu, SD; Blobe, GC; Xu, Y; Nguyen, S; Dua, R; Balcaitis, S; Gabitzsch, E; Balint, J; Jones, F; Lyerly, HK
MLA Citation
Morse, M, Hobeika, A, Chaudhry, A, Amalfitano, A, Niedzwiecki, D, Clay, TM, Osada, T, Devi, G, Burnett, BK, Weinhold, K, Hsu, SD, Blobe, GC, Xu, Y, Nguyen, S, Dua, R, Balcaitis, S, Gabitzsch, E, Balint, J, Jones, F, and Lyerly, HK. "Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.

INTRODUCTION: Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer. METHODS: We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA). RESULTS: Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer. CONCLUSIONS: Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease.

Authors
Cheng, Q; Chang, JT; Geradts, J; Neckers, LM; Haystead, T; Spector, NL; Lyerly, HK
MLA Citation
Cheng, Q, Chang, JT, Geradts, J, Neckers, LM, Haystead, T, Spector, NL, and Lyerly, HK. "Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer. (Published online)" Breast Cancer Res 14.2 (April 17, 2012): R62-.
PMID
22510516
Source
pubmed
Published In
Breast Cancer Research
Volume
14
Issue
2
Publish Date
2012
Start Page
R62
DOI
10.1186/bcr3168

Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected].

BACKGROUND: Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. METHODS: We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured. RESULTS: This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%). CONCLUSIONS: dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. TRIAL REGISTRY: ClinicalTrials.gov NCT00952692.

Authors
Hamilton, E; Blackwell, K; Hobeika, AC; Clay, TM; Broadwater, G; Ren, X-R; 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, X-R, Chen, W, Castro, H, Lehmann, F, Spector, N, Wei, J, Osada, T, Lyerly, HK, and Morse, MA. "Phase 1 clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibition [corrected]. (Published online)" J Transl Med 10 (February 10, 2012): 28-.
PMID
22325452
Source
pubmed
Published In
Journal of Translational Medicine
Volume
10
Publish Date
2012
Start Page
28
DOI
10.1186/1479-5876-10-28

Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer.

447 Background: Current biomarkers for colorectal cancer sub-classify tumors based on single mutations, such as KRAS; however, studies of single mutations belie the molecular complexity of colorectal cancer in which an average of 14 key genes per tumor is dysregulated. We hypothesize that colorectal cancer may be molecularly sub-classified based on an oncogenic pathway prediction model in which tumors are grouped based on patterns of oncogenic pathway dysregulation/expression.Affymetrix microarray data from 850 patients with primary colorectal cancer from publically available datasets were combined using Bayesian factor regression modeling normalization. The activity of 19 separate oncogenic pathways was predicted among tumors to generate patterns of pathway activity for each sample. Mixture modeling was applied to these samples to identify subgroups of tumors with unique patterns of pathway dysregulation. Validation of subclasses was performed on a dataset of 133 primary and metastatic colorectal cancer samples of patients undergoing curative surgical resection at our institution. Tumors were subgrouped according to our previous model and recurrence free survival was calculated. In vivo validation was performed by treating NOD/SCID mice bearing patient derived tumors with everolimus with changes in tumor size calculated between day 0 and day 21.Mixture modeling resulted in 6 individual subgroups of colorectal cancer based on pathway dysregulation. Kaplan Meier curves revealed that patients in subclass 4 had the poorest prognosis while patients in subclass 6 had the best prognosis (p=0.05). Further, tumors in subclass 4 were generally enriched for high mTOR pathway activation and patient derived explants from subclass 4 with high predicted mTOR activity were found to be sensitive to the MTOR pathway inhibitor everolimus.Prediction of oncogenic signaling pathway activity is a powerful tool that may be used to molecularly sub-classify colorectal cancer into biologically relevant subgroups. These subgroups have prognostic and predictive implications for recurrence following surgical resection and responsiveness to targeted therapy.

Authors
VanDeusen, JB; Uronis, J; Morse, M; Gatza, ML; Datto, MB; Mantyh, C; Lyerly, HK; Nevins, JR; Clary, BM; Hsu, SD
MLA Citation
VanDeusen, JB, Uronis, J, Morse, M, Gatza, ML, Datto, MB, Mantyh, C, Lyerly, HK, Nevins, JR, Clary, BM, and Hsu, SD. "Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.4_suppl (February 2012): 447-.
PMID
27983186
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
447

Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis.

480 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Curative treatment for CRC liver metastasis can be achieved by surgical resection, but 5 year survival ranges between 20-40%. Current treatment strategies to prevent recurrences after resection of CRC liver metastases have focused on the use of chemotherapy cytotoxic to malignant epithelial cells of the tumor. However, stromal components within the tumor microenvironment have recently been implicated as contributors to the aggressiveness of the malignancy. We hypothesized that genomic based signatures associated with tumor stroma would be prognostic for recurrence after CRC hepatic metastasectomy.Thirteen independent CRC liver metastatic samples were subjected to laser-capture microdissection to isolate the tumor epithelium and tumor-associated stroma separately. Microarray analysis using class neighbors and gene set enrichment analysis (GSEA) was applied to the stromal mRNA to identify differentially expressed genes and pathways between samples from patients with early recurrence (<1yr) after resection (Group R) and those who remain disease free (>2yrs) (Group NoR).Class neighbor analysis revealed a greater number of genes associated with immunity and cell to cell adhesion in Group R compared to Group NoR (p<0.05). Using GSEA, gene sets associated with T-cell immunity, Wnt pathway, and homeostasis were enriched in stroma Group R when compared to stroma Group NoR (p<0.05).These findings suggest several pathways are prognostic for recurrence of CRC liver metastasis. Development of stroma-directed therapy combined with tumor-directed therapy in preclinical models could hold the promise of major advances in the treatment of colorectal cancer liver metastasis in order to improve the clinical outcomes of these patients.

Authors
Rhodes, TD; Morse, M; Lyerly, HK; Nevins, JR; Clary, BM; Hsu, SD
MLA Citation
Rhodes, TD, Morse, M, Lyerly, HK, Nevins, JR, Clary, BM, and Hsu, SD. "Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30.4_suppl (February 2012): 480-.
PMID
27982957
Source
epmc
Published In
Journal of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
480

Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer.

Authors
VanDeusen, JB; Uronis, J; Morse, M; Gatza, ML; Datto, MB; Mantyh, C; Lyerly, HK; Nevins, JR; Clary, BM; Hsu, SD
MLA Citation
VanDeusen, JB, Uronis, J, Morse, M, Gatza, ML, Datto, MB, Mantyh, C, Lyerly, HK, Nevins, JR, Clary, BM, and Hsu, SD. "Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer." Journal of Clinical Oncology 30.4_suppl (February 2012): 447-447.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
447
End Page
447
DOI
10.1200/jco.2012.30.4_suppl.447

Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis.

Authors
Rhodes, TD; Morse, M; Lyerly, HK; Nevins, JR; Clary, BM; Hsu, SD
MLA Citation
Rhodes, TD, Morse, M, Lyerly, HK, Nevins, JR, Clary, BM, and Hsu, SD. "Discovering pathways in the tumor microenvironment important for recurrence-free survival in patients with colorectal liver metastasis." Journal of Clinical Oncology 30.4_suppl (February 2012): 480-480.
Source
crossref
Published In
Journal of Clinical Oncology
Volume
30
Issue
4_suppl
Publish Date
2012
Start Page
480
End Page
480
DOI
10.1200/jco.2012.30.4_suppl.480

ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.

Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H(2)DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H(2)O(2) and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H(2)O(2), and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.

Authors
Aird, KM; Allensworth, JL; Batinic-Haberle, I; Lyerly, HK; Dewhirst, MW; Devi, GR
MLA Citation
Aird, KM, Allensworth, JL, Batinic-Haberle, I, Lyerly, HK, Dewhirst, MW, and Devi, GR. "ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells." Breast Cancer Res Treat 132.1 (February 2012): 109-119.
PMID
21559822
Source
pubmed
Published In
Breast Cancer Research and Treatment
Volume
132
Issue
1
Publish Date
2012
Start Page
109
End Page
119
DOI
10.1007/s10549-011-1568-1

Evaluating the number of stages in development of squamous cell and adenocarcinomas across cancer sites using human population-based cancer modeling.

BACKGROUND: Adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) differ by clinical and molecular characteristics. We evaluated the characteristics of carcinogenesis by modeling the age patterns of incidence rates of ACs and SCCs of various organs to test whether these characteristics differed between cancer subtypes. METHODOLOGY/PRINCIPAL FINDINGS: Histotype-specific incidence rates of 14 ACs and 12 SCCs from the SEER Registry (1973-2003) were analyzed by fitting several biologically motivated models to observed age patterns. A frailty model with the Weibull baseline was applied to each age pattern to provide the best fit for the majority of cancers. For each cancer, model parameters describing the underlying mechanisms of carcinogenesis including the number of stages occurring during an individual's life and leading to cancer (m-stages) were estimated. For sensitivity analysis, the age-period-cohort model was incorporated into the carcinogenesis model to test the stability of the estimates. For the majority of studied cancers, the numbers of m-stages were similar within each group (i.e., AC and SCC). When cancers of the same organs were compared (i.e., lung, esophagus, and cervix uteri), the number of m-stages were more strongly associated with the AC/SCC subtype than with the organ: 9.79±0.09, 9.93±0.19 and 8.80±0.10 for lung, esophagus, and cervical ACs, compared to 11.41±0.10, 12.86±0.34 and 12.01±0.51 for SCCs of the respective organs (p<0.05 between subtypes). Most SCCs had more than ten m-stages while ACs had fewer than ten m-stages. The sensitivity analyses of the model parameters demonstrated the stability of the obtained estimates. CONCLUSIONS/SIGNIFICANCE: A model containing parameters capable of representing the number of stages of cancer development occurring during individual's life was applied to the large population data on incidence of ACs and SCCs. The model revealed that the number of m-stages differed by cancer subtype being more strongly associated with ACs/SCCs histotype than with organ/site.

Authors
Kravchenko, J; Akushevich, I; Abernethy, AP; Lyerly, HK
MLA Citation
Kravchenko, J, Akushevich, I, Abernethy, AP, and Lyerly, HK. "Evaluating the number of stages in development of squamous cell and adenocarcinomas across cancer sites using human population-based cancer modeling." PloS one 7.5 (January 2012): e37430-.
PMID
22629394
Source
epmc
Published In
PloS one
Volume
7
Issue
5
Publish Date
2012
Start Page
e37430
DOI
10.1371/journal.pone.0037430

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

Recombinant human endostatin could eliminate the pro-angiogenesis priority of SP cells sorted from non-small cell lung cancer cells

Purpose: To ascertain the biologic significance of lung cancer Side population (SP) cells, which represent putative cancer stem cells (CSC) in the absence of consensus biomarkers for tumor-specific CSC. Materials and methods: We sorted and analyzed the angiogenic features of SP cells, isolated from tumor cell lines based on the exclusion of the DNA dye Hoechst 33342, from the NSCLC cell lines A549 and H460. Results: Compared with non-SP cells, mRNA of vascular endothelial growth factor (VEGF)-A, VEGF-B, angiopoietin (ang)-1, ang-2, fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8) were over-expressed in SP cells accompanied by over-expression of ABCG2 and MDR1 mRNA. The supernatant of cultured SP cells could significantly induce migration of human umbilical vein endothelial cells, while recombinant human endostatin (Endostar 25®) could inhibit the migration. Conclusions: This study revealed that the NSCLC SP cells might represent CSCs and possess pro-angiogenic properties, and antiangiogenesis represent a potential therapy. © Federacion de Sociedades Españolas de Oncología (FESEO) 2012.

Authors
Cao, B; Jia, J; Ma, L; Di, L; Song, G; Yuan, Y; Ma, B; Zhu, Y; Yu, J; Wang, X; Zhou, X; Lyerly, HK; Ren, J
MLA Citation
Cao, B, Jia, J, Ma, L, Di, L, Song, G, Yuan, Y, Ma, B, Zhu, Y, Yu, J, Wang, X, Zhou, X, Lyerly, HK, and Ren, J. "Recombinant human endostatin could eliminate the pro-angiogenesis priority of SP cells sorted from non-small cell lung cancer cells." Clinical and Translational Oncology 14.8 (2012): 575-585.
PMID
22855139
Source
scival
Published In
Clinical and Translational Oncology
Volume
14
Issue
8
Publish Date
2012
Start Page
575
End Page
585
DOI
10.1007/s12094-012-0844-9

Non-genetic risk factors and predicting efficacy for docetaxel-drug-induced liver injury among metastatic breast cancer patients

Background and Aim: Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel-drug-induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear. Methods: We conducted a retrospective cohort study to identify non-genetic risk factors for docetaxel-DILI among 647 metastasis breast cancer patients treated with docetaxel-containing regimens. Results: Sixty-seven (10.36%) patients were diagnosed as docetaxel-DILI. By logistic regression analysis, premenopausal status (odds ratio [OR][95% confidence interval {CI}]=2.24 [1.30-3.87]), past hepatitis B virus (HBV) infections (OR [95% CI]=4.23 [1.57-11.42]), liver metastasis (OR [95% CI]=3.70 [2.16-6.34]). The predominant occurrence of DILI was seen in groups with docetaxel combination regimens. (OR [95% CI]=2.66 [1.59-4.55]). The potential increasing occurrence of docetaxel-DILI was associated with multiple risk factors in an exposure-response manner (P<0.001), and patients with more than three risk factors would be exposed to a 36.61-fold risk of DILI (95% CI=10.18-131.62). Further analysis by the risk score and area under the receiver-operator characteristic curve (AUC) showed that those four factors contributed to an AUC of 0.7536 (95% CI=0.70-0.81), with a predictive sensitivity of 74.63% and specificity of 65.17%. Conclusions: Docetaxel-DILI with a relatively higher incidence should be addressed among metastatic breast cancer patients. Four predominant risk factors, including premenopausal status, past HBV infection, liver metastasis, and docetaxel combination regimens, were potential predicators for DILI. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Authors
Wang, Z; Liang, X; Yu, J; Zheng, X; Zhu, Y; Yan, Y; Dong, N; Di, L; Song, G; Zhou, X; Wang, X; Yang, H; Ren, J; Lyerly, HK
MLA Citation
Wang, Z, Liang, X, Yu, J, Zheng, X, Zhu, Y, Yan, Y, Dong, N, Di, L, Song, G, Zhou, X, Wang, X, Yang, H, Ren, J, and Lyerly, HK. "Non-genetic risk factors and predicting efficacy for docetaxel-drug-induced liver injury among metastatic breast cancer patients." Journal of Gastroenterology and Hepatology (Australia) 27.8 (2012): 1348-1352.
PMID
22432938
Source
scival
Published In
Journal of Gastroenterology and Hepatology
Volume
27
Issue
8
Publish Date
2012
Start Page
1348
End Page
1352
DOI
10.1111/j.1440-1746.2012.07131.x

Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients

Aim: This study was designed to explore the genetic polymorphism of IL-10 (-1082A/G, -592A/C, -819T/C), TNF-α (-308G/A) with susceptibility to docetaxel-induced liver injury (DILI) in Chinese breast cancer patients. Methods: The targeted genetic polymorphisms of IL10-1082G/A, IL10-592A/C, IL10-819T/C, TNF-308G/A from 40 patients with DILI were assayed by matrix-assisted laser desorption/ionization-time of flight of Sequenom. Results: AA genotype of IL10-592 and TT of IL10-819 significantly increased incidence of DILI (P = 0.005, OR = 3.137). No differences of TNF gene polymorphism between the two groups were seen. Conclusion: The genetic polymorphism of the IL10-592A/C AA genotype and IL10-819T/C TT genotype was predominantly conferred to the incidence of docetaxel-induced liver injury. © 2012 Federación de Sociedades Españolas de Oncología (FESEO).

Authors
Liang, X; Zhang, J; Zhu, Y; Lu, Y; Zhou, X; Wang, Z; Yu, J; Yan, Y; Di, L; Che, L; al, E
MLA Citation
Liang, X, Zhang, J, Zhu, Y, Lu, Y, Zhou, X, Wang, Z, Yu, J, Yan, Y, Di, L, Che, L, and al, E. "Specific genetic polymorphisms of IL10-592 AA and IL10-819 TT genotypes lead to the key role for inducing docetaxel-induced liver injury in breast cancer patients." Clinical and Translational Oncology (2012): 1-4.
PMID
23143946
Source
scival
Published In
Clinical and Translational Oncology
Publish Date
2012
Start Page
1
End Page
4
DOI
10.1007/s12094-012-0936-6

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

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

Need for global partnership in cancer care: perceptions of cancer care researchers attending the 2010 australia and Asia pacific clinical oncology research development workshop.

PURPOSE: To understand the diversity of issues and the breadth of growing clinical care, professional education, and clinical research needs of developing countries, not typically represented in Western or European surveys of cancer care and research. METHODS: A cross-sectional survey was conducted of the attendees at the 2010 Australia and Asia Pacific Clinical Oncology Research Development workshop (Queensland, Australia) about the most important health care questions facing the participant's home countries, especially concerning cancer. RESULTS: Early-career oncologists and advanced oncology trainees from a region of the world containing significant low- and middle-income countries reported that cancer is an emerging health priority as a result of aging of the population, the impact of diet and lifestyle, and environmental pollution. There was concern about the capacity of health care workers and treatment facilities to provide cancer care and access to the latest cancer therapies and technologies. Although improving health care delivery was seen as a critical local agenda priority, focusing on improved cancer research activities in this select population was seen as the best way that others outside the country could improve outcomes for all. CONCLUSIONS: The burden of cancer will increase dramatically over the next 20 years, particularly in countries with developing and middle-income economies. Cancer research globally faces significant barriers, many of which are magnified in the developing country setting. Overcoming these barriers will require partnerships sensitive and responsive to both local and global needs.

Authors
Lyerly, HK; Abernethy, AP; Stockler, MR; Koczwara, B; Aziz, Z; Nair, R; Seymour, L
MLA Citation
Lyerly, HK, Abernethy, AP, Stockler, MR, Koczwara, B, Aziz, Z, Nair, R, and Seymour, L. "Need for global partnership in cancer care: perceptions of cancer care researchers attending the 2010 australia and Asia pacific clinical oncology research development workshop." J Oncol Pract 7.5 (September 2011): 324-329.
PMID
22211131
Source
pubmed
Published In
Journal of Oncology Practice
Volume
7
Issue
5
Publish Date
2011
Start Page
324
End Page
329
DOI
10.1200/JOP.2011.000230

Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors.

ErbB2 tyrosine kinase inhibitors (TKI) block tyrosine autophosphorylation and activation of the full-length transmembrane ErbB2 receptor (p185(ErbB2)). In addition to p185(ErbB2), truncated forms of ErbB2 exist in breast cancer cell lines and clinical tumors. The contribution of these truncated forms, specifically those expressed in tumor cell nuclei, to the development of therapeutic resistance to ErbB2 TKIs has not been previously shown. Here, we show that expression of a 95-kDa tyrosine phosphorylated form of ErbB2, herein referred to as p95L (lapatinib-induced p95) was increased in ErbB2(+) breast cancer cells treated with potent ErbB2 TKIs (lapatinib, GW2974). Expressed in tumor cell nuclei, tyrosine phosphorylation of p95L was resistant to inhibition by ErbB2 TKIs. Furthermore, the expression of p95L was increased in ErbB2(+) breast cancer models of acquired therapeutic resistance to lapatinib that mimic the clinical setting. Pretreatment with proteasome inhibitors blocked p95L induction in response to ErbB2 TKIs, implicating the role of the proteasome in the regulation of p95L expression. In addition, tyrosine phosphorylated C-terminal fragments of ErbB2, generated by alternate initiation of translation and similar in molecular weight to p95L, were expressed in tumor cell nuclei, where they too were resistant to inhibition by ErbB2 TKIs. When expressed in the nuclei of lapatinib-sensitive ErbB2(+) breast cancer cells, truncated ErbB2 rendered cells resistant to lapatinib-induced apoptosis. Elucidating the function of nuclear, truncated forms of ErbB2, and developing therapeutic strategies to block their expression and/or activation may enhance the clinical efficacy of ErbB2 TKIs.

Authors
Xia, W; Liu, Z; Zong, R; Liu, L; Zhao, S; Bacus, SS; Mao, Y; He, J; Wulfkuhle, JD; Petricoin, EF; Osada, T; Yang, X-Y; Hartman, ZC; Clay, TM; Blackwell, KL; Lyerly, HK; Spector, NL
MLA Citation
Xia, W, Liu, Z, Zong, R, Liu, L, Zhao, S, Bacus, SS, Mao, Y, He, J, Wulfkuhle, JD, Petricoin, EF, Osada, T, Yang, X-Y, Hartman, ZC, Clay, TM, Blackwell, KL, Lyerly, HK, and Spector, NL. "Truncated ErbB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ErbB2 kinase inhibitors." Mol Cancer Ther 10.8 (August 2011): 1367-1374.
PMID
21673090
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
10
Issue
8
Publish Date
2011
Start Page
1367
End Page
1374
DOI
10.1158/1535-7163.MCT-10-0991

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

Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms.

The observed bimodal patterns of breast cancer incidence in the U.S. suggested that breast cancer may be viewed as more than one biological entity. We studied the factors potentially contributing to this phenomenon, specifically focusing on how disease heterogeneity could be linked to breast carcinogenesis mechanisms. Using empirical analyses and population-based biologically motivated modeling, age-specific patterns of incidence of ductal and lobular breast carcinomas from the SEER registry (1990-2003) were analyzed for heterogeneity and characteristics of carcinogenesis, stratified by race, stage, grade, and estrogen (ER)/progesterone (PR) receptor status. The heterogeneity of breast carcinoma age patterns decreased after stratification by grade, especially for grade I and III tumors. Stratification by ER/PR status further reduced the heterogeneity, especially for ER(+)/PR(-) and ER(-)/(-) tumors; however, the residual heterogeneity was still observed. The number of rate-limiting events of carcinogenesis and the latency of ductal and lobular carcinomas differed, decreasing from grade I to III, with poorly differentiated tumors associated with the least number of carcinogenesis stages and the shortest latency. Tumor grades play important role in bimodal incidence of breast carcinoma and have distinct mechanisms of carcinogenesis. Race and cancer subtype could play modifying role. ER/PR status contributes to the observed heterogeneity, but is subdominant to tumor grade. Further studies on sources of "remaining" heterogeneity of population with breast cancer (such as genetic/epigenetic characteristics) are necessary. The results of this study could suggest stratification rather than unification of breast cancer prevention strategies, risk assessment, and treatment.

Authors
Kravchenko, J; Akushevich, I; Seewaldt, VL; Abernethy, AP; Lyerly, HK
MLA Citation
Kravchenko, J, Akushevich, I, Seewaldt, VL, Abernethy, AP, and Lyerly, HK. "Breast cancer as heterogeneous disease: contributing factors and carcinogenesis mechanisms." Breast cancer research and treatment 128.2 (July 2011): 483-493.
PMID
21225455
Source
epmc
Published In
Breast Cancer Research and Treatment
Volume
128
Issue
2
Publish Date
2011
Start Page
483
End Page
493
DOI
10.1007/s10549-011-1347-z

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

Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls

Authors
Morse, M; Niedzwiecki, D; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, A; Osada, T; Clary, BM; Hsu, SD; Devi, G; Bulusu, A; Annechiarico, R; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Niedzwiecki, D, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, A, Osada, T, Clary, BM, Hsu, SD, Devi, G, Bulusu, A, Annechiarico, R, Chadaram, V, Clay, TM, and Lyerly, HK. "Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls." May 20, 2011.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study.

Authors
Lyerly, HK; Hobeika, A; Niedzwiecki, D; Osada, T; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hsu, SD; Bulusu, A; Clary, BM; Annechiarico, R; Devi, G; Chadaram, V; Clay, TM; Morse, M
MLA Citation
Lyerly, HK, Hobeika, A, Niedzwiecki, D, Osada, T, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hsu, SD, Bulusu, A, Clary, BM, Annechiarico, R, Devi, G, Chadaram, V, Clay, TM, and Morse, M. "A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study." May 20, 2011.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

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

Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients. METHODS: The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays. RESULTS: Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement. CONCLUSION: Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.

Authors
Thomas, ZI; Gibson, W; Sexton, JZ; Aird, KM; Ingram, SM; Aldrich, A; Lyerly, HK; Devi, GR; Williams, KP
MLA Citation
Thomas, ZI, Gibson, W, Sexton, JZ, Aird, KM, Ingram, SM, Aldrich, A, Lyerly, HK, Devi, GR, and Williams, KP. "Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration." Br J Cancer 104.10 (May 10, 2011): 1575-1586.
PMID
21505458
Source
pubmed
Published In
British Journal of Cancer
Volume
104
Issue
10
Publish Date
2011
Start Page
1575
End Page
1586
DOI
10.1038/bjc.2011.133

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

A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study.

2533 Background: CD8+ T cell responses to colorectal cancer are associated with longer survival. This has led to the hypothesis that cancer vaccines, capable of activating T cell responses, may improve clinical outcome. Vaccines based on antigen-presenting cells/dendritic cells (DC) and viral vectors, potent stimulators of adaptive immunity, have been associated with enhanced survival in prostate cancer patients. We compared rates of tumor antigen-specific T cell and antibody responses between a DC and a poxvector vaccine. The clinical outcome data is reported elsewhere.74 patients with no evidence of disease after colorectal cancer metastasectomy and completion of peri-operative chemotherapy were randomized 1:1 to receive injections of one of either: DC mixed with PANVAC-VF (poxvectors encoding CEA, MUC1, CD54, CD58, CD80) or PANVAC-VF along with local injections of GM-CSF. Peripheral blood was drawn before and after completing the immunizations for analysis of CEA and MUC-1 immune (T cell and antibody) responses by ELISPOT and ELISA.T cell responses against CEA were significantly more frequent in the DC arm (69 versus 41%, p=0.02) although the magnitude of the T cell response among responders was similar. There was a trend for improved relapse-free survival among patients with CEA-specific T cell responses (log rank p = 0.10). The antibody response to CEA was more frequent with the PANVAC alone (100% versus 67%, (p= 0.018)) and the antibodies in serum from vaccinated patients could bind to CEA-expressing tumor cells and mediated ADCC. No antibody response was induced against MUC-1. The antibody response against CEA did not correlate with clinical benefit. Few deaths were observed limiting comparison of survival by immune response.A dendritic cell vaccine leads to a greater frequency of CEA-specific T cell responses which is associated with enhanced RFS. Ongoing studies are evaluating the role of additional immunostimulatory cytokines and modulation of regulatory cell populations and molecules in enhancing the adaptive immune response to the DC-based vaccine.

Authors
Lyerly, HK; Hobeika, A; Niedzwiecki, D; Osada, T; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hsu, SD; Bulusu, A; Clary, BM; Annechiarico, R; Devi, G; Chadaram, V; Clay, TM; Morse, M
MLA Citation
Lyerly, HK, Hobeika, A, Niedzwiecki, D, Osada, T, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hsu, SD, Bulusu, A, Clary, BM, Annechiarico, R, Devi, G, Chadaram, V, Clay, TM, and Morse, M. "A dendritic cell-based vaccine effects on T-cell responses compared with a viral vector vaccine when administered to patients following resection of colorectal metastases in a randomized phase II study." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 2533-.
PMID
28022328
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
2533

Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls.

3557 Background: Patients with completely resected metastases from colorectal cancer (CRC) remain at high risk of recurrence and death despite adjuvant chemotherapy. Recently, survival of prostate cancer patients was enhanced by antigen-presenting cell therapy. We investigated whether administration of an antigen-presenting cell vaccine based on dendritic cells (DC) after metastasectomy would reduce the risk of recurrence and increase survival.Patients (n=74) with no evidence of disease after resection of CRC metastases and completion of their physician-determined peri-operative chemotherapy were randomized 1:1 to four immunizations with: DC modified with the PANVAC-VF poxvectors encoding CEA, MUC1, CD54, CD58, and CD80 or the PANVAC-VF poxvectors along with GM-CSF at the injection site. We report recurrence-free survival (RFS) at 2 years and overall survival (OS). CEA specific T cell responses were measured by ELISPOT. Data from a prospectively registered, comparable, contemporary control group of patients who had undergone metastasectomy for CRC were also available.The arms of the study and contemporary controls were well balanced. The majority of the toxicities for the DC and PANVAC arms respectively were grade 1, 2 injection site reactions (63% versus 64%), low grade fevers (17% vs 31%), myalgia (11% vs 11%), and fatigue (26% vs 34%). The two year RFS was similar in all groups (50, 56 and 55% for the DC arm, the PANVAC arm and the contemporary control group, respectively). However, there was a trend for improved RFS among patients with CEA-specific T cell responses (log rank p = 0.10). At a median follow-up of 40 months, 2 of 37 patients treated with DC and 5 of 37 treated with PANVAC alone have died, with a combined survival rate exceeding that of the unvaccinated control patients.Patients vaccinated after metastasectomy experienced a longer survival relative to contemporary controls. A phase III study of OS comparing patients vaccinated after resection with the DC vaccine and observation is warranted.

Authors
Morse, M; Niedzwiecki, D; Marshall, J; Garrett, CR; Chang, DZ; Aklilu, M; Crocenzi, TS; Cole, DJ; Dessureault, S; Hobeika, A; Osada, T; Clary, BM; Hsu, SD; Devi, G; Bulusu, A; Annechiarico, R; Chadaram, V; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Niedzwiecki, D, Marshall, J, Garrett, CR, Chang, DZ, Aklilu, M, Crocenzi, TS, Cole, DJ, Dessureault, S, Hobeika, A, Osada, T, Clary, BM, Hsu, SD, Devi, G, Bulusu, A, Annechiarico, R, Chadaram, V, Clay, TM, and Lyerly, HK. "Survival rates among patients vaccinated following resection of colorectal cancer metastases in a phase II randomized study compared with contemporary controls." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 3557-.
PMID
28020295
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
3557

Role of the type III TGF-β receptor in modulating antitumor immunity during breast cancer progression.

10540 Background: We have shown that breast cancers downregulate the expression of the type III TGF-β receptor (TβRIII) tumor suppressor during tumor progression. Previous work has shown TβRIII to undergo ectodomain shedding, enabling the sequestration of the soluble TGF-β ligand and the inhibition of the TGF-β signaling pathway.  The TGF-β cytokine inhibits dendritic cell (DC)-dependent antigen presentation.  We hypothesize that the downregulation of TβRIII during breast tumor development permits enhanced TGF-β signaling within the local DCs of the tumor microenvironment allowing the tumor to evade the host immune response.Our data suggest that the tumor suppressor properties of TβRIII in the 4T1 murine metastatic breast cancer model are diminished in immunosuppressed hosts. Indeed, loss of TβRIII allows for the progression of more immunogenic Her2/neu-expressing 4T1 tumors and suppresses Her2/neu-specific T cell responses. Flow cytometry and rt-PCR studies indicate that breast tumors which lack TβRIII expression exhibit reduced numbers of infiltrating CD8+ T cells and increased regulatoy T cells (Tregs), findings which are supported by human microarray data. In addition, DCs within TβRIIIlo tumors and their draining lymph nodes (TDLNs) express enhanced levels of the indoleamine 2,3-dioxygenase (IDO) enzyme as well as the CCL22 chemokine, which correlates with expanded local Treg populations. Studies have shown 4T1-RIII conditioned media to inhibit TGF-β signaling within DCs and to suppress the TGF-β-mediated inhibition of DC maturation. Our work is showing that DCs within the TDLNs of TβRIIIhi tumors exhibit a more mature phenotype.The increased TGF-β signaling capacity of DCs residing in TβRIIIlo tumors may allow for increased local CCL22 expression; thereby promoting Treg recruitment and allowing for CTLA-4-mediated IDO upregulation by local DCs.This pathway represents a novel mechanism for evading the host anti-tumor immune response, supports the targeting of TGF-β as a strategy to enhance the efficacy of immunotherapeutic approaches for solid tumors, and suggests that serum levels of soluble TβRIII may represent a useful biomarker for immunotherapy.

Authors
Hanks, BA; Campbell, OM; Lee, JD; Morse, M; Clay, TM; Lyerly, HK; Blobe, GC
MLA Citation
Hanks, BA, Campbell, OM, Lee, JD, Morse, M, Clay, TM, Lyerly, HK, and Blobe, GC. "Role of the type III TGF-β receptor in modulating antitumor immunity during breast cancer progression." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 10540-.
PMID
28021827
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
10540

Correlates of quality of life-related outcomes in breast cancer patients participating in the Pathfinders pilot study.

OBJECTIVE: In a pilot study, participation in the Pathfinders program was associated with reductions in distress and despair and improvements in quality of life (QOL) among advanced breast cancer patients. This study explores the relationship between psychosocial resources invoked through the Pathfinders intervention and outcomes. METHODS: Advanced breast cancer patients were enrolled in a prospective, single-arm, pilot study of the Pathfinders psychosocial program. Participants met at least monthly with a licensed clinical social worker who administered the Pathfinders intervention, which focused on strengthening adaptive coping skills, identifying inner strengths, and developing a self-care plan. Longitudinal assessments over 6 months used validated instruments to assess changes in Pathfinders targets (coping, social support, self-efficacy, spirituality, and optimism) and outcomes (distress, despair, QOL, and fatigue). Multiple linear regression models examined the joint effect of average changes in target subscales on average outcome changes, adjusted for baseline outcome scores and patient characteristics. RESULTS: Participants (n=44) were: mean age 51 (SD, 12), 20% non-Caucasian, 50% college degree, and 75% married. Improvements in active coping skills, self-efficacy, and spiritual meaning/peace significantly correlated with an improvement in despair after adjustment for demographic characteristics (all P<0.05). Improvements in social support significantly correlated with positive changes in distress (P<0.05). Gains in learned optimism independently correlated with an increase in overall QOL (P<0.01). CONCLUSIONS: In this pilot assessment, changes in pre-defined Pathfinders targets such as coping skills, social support, self-efficacy, spirituality, and optimism correlated with improvements in patient-reported outcomes.

Authors
Smith, SK; Herndon, JE; Lyerly, HK; Coan, A; Wheeler, JL; Staley, T; Abernethy, AP
MLA Citation
Smith, SK, Herndon, JE, Lyerly, HK, Coan, A, Wheeler, JL, Staley, T, and Abernethy, AP. "Correlates of quality of life-related outcomes in breast cancer patients participating in the Pathfinders pilot study." Psychooncology 20.5 (May 2011): 559-564.
PMID
20878862
Source
pubmed
Published In
Psycho-Oncology
Volume
20
Issue
5
Publish Date
2011
Start Page
559
End Page
564
DOI
10.1002/pon.1770

CANDIDATE HEDGEHOG/SMOOTHENED INHIBITORS FOR PEDIATRIC MEDULLOBLASTOMA

Authors
Wang, J; Mook, R; Lyerly, HK; Barak, L; Chen, W
MLA Citation
Wang, J, Mook, R, Lyerly, HK, Barak, L, and Chen, W. "CANDIDATE HEDGEHOG/SMOOTHENED INHIBITORS FOR PEDIATRIC MEDULLOBLASTOMA." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I21
End Page
I21

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

Development of an assay to predict oxaliplatin sensitivity from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues

Authors
Freedman, JA; Osada, T; Tsamis, KA; Morse, M; Clary, BM; Lyerly, HK; Nevins, JR; Clay, TM; Hsu, SD
MLA Citation
Freedman, JA, Osada, T, Tsamis, KA, Morse, M, Clary, BM, Lyerly, HK, Nevins, JR, Clay, TM, and Hsu, SD. "Development of an assay to predict oxaliplatin sensitivity from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues." February 1, 2011.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
4
Publish Date
2011

Development of an assay to predict oxaliplatin sensitivity from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues.

429 Background: Genomic profiling has improved our understanding of the underlying biology of tumors, accuracy of diagnosing disease, predictions of the courses of disease, and ability to determine the therapeutic agents that will be most effective in the treatment of particular tumors. However, in order for assays involving microarray data to be useful in the clinical setting, the ability to generate reliable and consistent data from FFPE tissues is essential.Cancer cell lines from the NCI-60 collection exhibiting greatest sensitivity or resistance to oxaliplatin were identified. These cells were grown in culture, fixed for 24 hours in formalin, and paraffin-embedded. RNA from the FFPE cells was isolated, amplified, and hybridized to Affymetrix arrays. A Bayesian binary regression analysis was used to generate a predictor of oxaliplatin sensitivity from the gene expression data. Metastatic derived xenografts (MDXs) from resected colorectal tumors were established and treated with oxaliplatin. Samples from tumors prior to treatment were paraffin-embedded and used for RNA extraction, amplification, and hybridization to Affymetrix arrays. The gene expression signature predicting sensitivity to oxaliplatin was then validated with response data from MDXs treated with oxaliplatin.A predictor consisting of 300 genes that could predict sensitivity to oxaliplatin was generated using FFPE samples. Significant correlation was observed between the predicted probability of oxaliplatin sensitivity and the tumor growth inhibition measurement for a given MDX (p=0.0012).Reliable and consistent predictions of oxaliplatin sensitivity can be obtained from gene expression data from FFPE tissues. This method has potential utility in the clinical setting. The ability to predict response to a therapeutic in a FFPE sample has the potential to guide the choice of therapeutics, resulting in an option that could be most effective in treating an individual with metastatic colorectal cancer. No significant financial relationships to disclose.

Authors
Freedman, JA; Osada, T; Tsamis, KA; Morse, M; Clary, BM; Lyerly, HK; Nevins, JR; Clay, TM; Hsu, SD
MLA Citation
Freedman, JA, Osada, T, Tsamis, KA, Morse, M, Clary, BM, Lyerly, HK, Nevins, JR, Clay, TM, and Hsu, SD. "Development of an assay to predict oxaliplatin sensitivity from formalin-fixed, paraffin-embedded (FFPE) colorectal cancer tissues." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.4_suppl (February 2011): 429-.
PMID
27985824
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
4_suppl
Publish Date
2011
Start Page
429

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

Erratum: Phase 2 pilot study of Pathfinders: A psychosocial intervention for cancer patients (Support Care Center DOI 10.1007/s00520-010-0823-z)

Authors
Abernethy, AP; II, JEH; Coan, A; Staley, T; Wheeler, JL; Rowe, K; Smith, SK; Shaw, H; Lyerly, HK
MLA Citation
Abernethy, AP, II, JEH, Coan, A, Staley, T, Wheeler, JL, Rowe, K, Smith, SK, Shaw, H, and Lyerly, HK. "Erratum: Phase 2 pilot study of Pathfinders: A psychosocial intervention for cancer patients (Support Care Center DOI 10.1007/s00520-010-0823-z)." Supportive Care in Cancer 19.3 (2011): 439--.
Source
scival
Published In
Supportive Care in Cancer
Volume
19
Issue
3
Publish Date
2011
Start Page
439-
DOI
10.1007/s00520-010-1076-6

CSPG4 protein as a new target for the antibody-based immunotherapy of triple-negative breast cancer.

BACKGROUND: The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)-based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb. METHODS: CSPG4 protein expression was assessed in 44 primary TNBC lesions, in TNBC cell lines HS578T, MDA-MB-231, MDA-MB-435, and SUM149, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. The effect of CSPG4-specific mAb 225.28 on growth, adhesion, and migration of TNBC cells was tested in vitro. The ability of mAb 225.28 to induce regression of tumor metastases (n = 7 mice) and to inhibit spontaneous metastasis and tumor recurrence (n = 12 mice per group) was tested in breast cancer models in mice. The mechanisms responsible for the antitumor effect of mAb 225.28 were also investigated in the cell lines and in the mouse models. All statistical tests were two-sided. RESULTS: CSPG4 protein was preferentially expressed in 32 of the 44 (72.7%) primary TNBC lesions tested, in TNBC cell lines, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 μm(2); difference of mean = 121360.0 μm(2), 95% confidence interval = 91010.7 to 151709.4 μm(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis. CONCLUSIONS: This study identified CSPG4 as a new target for TNBC. The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis.

Authors
Wang, X; Osada, T; Wang, Y; Yu, L; Sakakura, K; Katayama, A; McCarthy, JB; Brufsky, A; Chivukula, M; Khoury, T; Hsu, DS; Barry, WT; Lyerly, HK; Clay, TM; Ferrone, S
MLA Citation
Wang, X, Osada, T, Wang, Y, Yu, L, Sakakura, K, Katayama, A, McCarthy, JB, Brufsky, A, Chivukula, M, Khoury, T, Hsu, DS, Barry, WT, Lyerly, HK, Clay, TM, and Ferrone, S. "CSPG4 protein as a new target for the antibody-based immunotherapy of triple-negative breast cancer." J Natl Cancer Inst 102.19 (October 6, 2010): 1496-1512.
PMID
20852124
Source
pubmed
Published In
Journal of the National Cancer Institute
Volume
102
Issue
19
Publish Date
2010
Start Page
1496
End Page
1512
DOI
10.1093/jnci/djq343

Targeting Soluble Tumor Associated Antigens CEA and HER2 to Exosomes Enhances Antigen Specific Immune Reponses

Authors
Lyerly, HK; Le Pecq, JB; Hartman, Z; Clay, T; Delcayre, A; Murad, Y
MLA Citation
Lyerly, HK, Le Pecq, JB, Hartman, Z, Clay, T, Delcayre, A, and Murad, Y. "Targeting Soluble Tumor Associated Antigens CEA and HER2 to Exosomes Enhances Antigen Specific Immune Reponses." October 2010.
Source
wos-lite
Published In
Journal of Immunotherapy
Volume
33
Issue
8
Publish Date
2010
Start Page
879
End Page
879

Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity.

Although critical for initiating and regulating immune responses, the therapeutic use of individual cytokines as anticancer immunotherapeutic agents has achieved only modest clinical success. Consequently, many current strategies have focused on the use of specific immunotherapeutic agonists that engage individual receptors of innate immune networks, such as the Toll-like receptor (TLR) system, each resulting in specific patterns of gene expression, cytokine production, and inflammatory outcome. However, these immunotherapeutics are constrained by variable cellular TLR expression and responsiveness to particular TLR agonists, as well as the specific cellular context of different tumors. We hypothesized that overexpression of MyD88, a pivotal regulator of multiple TLR signaling pathways, could circumvent these constraints and mimic coordinated TLR signaling across all cell types in a ligand-independent fashion. To explore this hypothesis, we generated an adenoviral vector expressing MyD88 and show that Ad-MyD88 infection elicits extensive Th1-specific transcriptional and secreted cytokine signatures in all murine and human cell types tested in vitro and in vivo. Importantly, in vivo intratumoral injection of Ad-MyD88 into established tumor masses enhanced adaptive immune responses and inhibited local tumor immunosuppression, resulting in significantly inhibited local and systemic growth of multiple tumor types. Finally, Ad-MyD88 infection of primary human dendritic cells, tumor-associated fibroblasts, and colorectal carcinoma cells elicited significant Th1-type cytokine responses, resulting in enhanced tumor cell lysis and expansion of human tumor antigen-specific T cells. Thus, Ad-MyD88 initiated robust antitumor activity in established murine tumor microenvironments and in human contexts, suggesting its potential effectiveness as a clinical immunotherapeutic strategy.

Authors
Hartman, ZC; Osada, T; Glass, O; Yang, XY; Lei, G-J; Lyerly, HK; Clay, TM
MLA Citation
Hartman, ZC, Osada, T, Glass, O, Yang, XY, Lei, G-J, Lyerly, HK, and Clay, TM. "Ligand-independent toll-like receptor signals generated by ectopic overexpression of MyD88 generate local and systemic antitumor immunity." Cancer Res 70.18 (September 15, 2010): 7209-7220.
PMID
20823152
Source
pubmed
Published In
Cancer Research
Volume
70
Issue
18
Publish Date
2010
Start Page
7209
End Page
7220
DOI
10.1158/0008-5472.CAN-10-0905

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

Phase 2 pilot study of Pathfinders: a psychosocial intervention for cancer patients.

PURPOSE: Pathfinders is a multi-faceted psychosocial care program for cancer patients; it was developed in community oncology and adapted to the academic oncology setting. This prospective, single-arm, phase 2 pilot study examined the acceptability and feasibility of Pathfinders for women with metastatic breast cancer. METHODS: Over 3 months, participants completed patient-reported surveys including the Patient Care Monitor (PCM, review of systems), Functional Assessment of Chronic Illness Therapy-Breast Cancer (FACT-B), Self Efficacy, and a single-item survey asking patients whether the program was helpful to them. A technology-based data collection system was used to capture electronic patient-reported outcomes at point of care, report symptoms in real time to clinicians, and collect warehouse data to provide a detailed longitudinal picture of the patient experience when receiving Pathfinders. RESULTS: Participants (n = 50) were: mean age 51 (SD 11); 76% white, 20% black; 74% married; 50% college degree. Forty-two (n = 42) patients completed baseline and 3-month assessments. Statistically significant improvements (all P < 0.05) occurred in PCM subscales for Distress (mean [SE] = -3.42 [1.21]), Despair (-4.53 [1.56]), and Quality of Life (2.88 [0.97]), and the FACT-B Emotional Wellbeing subscale (2.07 [0.46]). Of the 29 participants asked if Pathfinders was helpful, 27 (93%) responded positively and two did not respond. Other instruments measuring symptoms, quality of life, and self-efficacy showed improvement. CONCLUSIONS: In a phase 2 pilot study, Pathfinders was helpful to patients and is feasible in an academic medical center. Follow-up data collected at the 3-month assessment suggest that the program impacts various psychological outcomes, notably distress and despair.

Authors
Abernethy, AP; Herndon, JE; Coan, A; Staley, T; Wheeler, JL; Rowe, K; Smith, SK; Shaw, H; Lyerly, HK
MLA Citation
Abernethy, AP, Herndon, JE, Coan, A, Staley, T, Wheeler, JL, Rowe, K, Smith, SK, Shaw, H, and Lyerly, HK. "Phase 2 pilot study of Pathfinders: a psychosocial intervention for cancer patients." Support Care Cancer 18.7 (July 2010): 893-898.
PMID
20143102
Source
pubmed
Published In
Supportive Care in Cancer
Volume
18
Issue
7
Publish Date
2010
Start Page
893
End Page
898
DOI
10.1007/s00520-010-0823-z

Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA.

Adenovirus serotype 5 (Ad5) has been widely used in clinical trials because it expresses inserted transgenes robustly and augments the innate immune response. Strategies to improve Ad5 vectors that can circumvent Ad5 immunity have become a critical issue, especially for use as a cancer immunotherapeutic in which repeated immunization is required. In this study, we constructed a novel Ad5 vector with unique deletions of the viral DNA polymerase and the pre-terminal protein region (Ad5 [E1-, E2b-]). This vector contains the carcinoembryonic antigen (CEA) gene insert and is designed to induce cell-mediated immunity (CMI) against the tumor-associated target. The CEA immunogenicity and in vivo anti-tumor effects of repeated immunizations with Ad5 [E1-, E2b-]-CEA compared with those observed with current generation Ad5 [E1-]-CEA were tested in Ad5 pre-immunized mice. We report that Ad5-immune mice immunized multiple times with Ad5 [E1-, E2b-]-CEA induced CEA-specific CMI responses that were significantly increased over those detected in Ad5-immune mice immunized multiple times with a current generation Ad5 [E1-]-CEA. Ad5 immune mice bearing CEA-expressing tumors that were treated with Ad5 [E1-, E2b-]-CEA had increased anti-tumor response as compared with Ad5 [E1-]-CEA treated mice. These results demonstrate that Ad5 [E1-, E2b-]-CEA can induce CMI immune responses which result in tumor growth inhibition despite the presence of pre-existing Ad5 immunity. Multiple re-immunizations using the same vector platform are now possible with the novel Ad5 [E1-, E2b-] platform.

Authors
Gabitzsch, ES; Xu, Y; Balint, JP; Hartman, ZC; Lyerly, HK; Jones, FR
MLA Citation
Gabitzsch, ES, Xu, Y, Balint, JP, Hartman, ZC, Lyerly, HK, and Jones, FR. "Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA." Cancer Immunol Immunother 59.7 (July 2010): 1131-1135.
PMID
20361185
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
59
Issue
7
Publish Date
2010
Start Page
1131
End Page
1135
DOI
10.1007/s00262-010-0847-8

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

Electronic patient-reported data capture as a foundation of rapid learning cancer care.

BACKGROUND: "Rapid learning healthcare" presents a new infrastructure to support comparative effectiveness research. By leveraging heterogeneous datasets (eg, clinical, administrative, genomic, registry, and research), health information technology, and sophisticated iterative analyses, rapid learning healthcare provides a real-time framework in which clinical studies can evaluate the relative impact of therapeutic approaches on a diverse array of measures. PURPOSE: This article describes an effort, at 1 academic medical center, to demonstrate what rapid learning healthcare might look like in operation. The article describes the process of developing and testing the components of this new model of integrated clinical/research function, with the pilot site being an academic oncology clinic and with electronic patient-reported outcomes (ePROs) being the foundational dataset. RESEARCH DESIGN: Steps included: feasibility study of the ePRO system; validation study of ePRO collection across 3 cancers; linking ePRO and other datasets; implementation; stakeholder alignment and buy in, and; demonstration through use cases. SUBJECTS: Two use cases are presented; participants were metastatic breast cancer (n = 65) and gastrointestinal cancer (n = 113) patients at 2 academic medical centers. RESULTS: (1) Patient-reported symptom data were collected with tablet computers; patients with breast and gastrointestinal cancer indicated high levels of sexual distress, which prompted multidisciplinary response, design of an intervention, and successful application for funding to study the intervention's impact. (2) The system evaluated the longitudinal impact of a psychosocial care program provided to patients with breast cancer. Participants used tablet computers to complete PRO surveys; data indicated significant impact on psychosocial outcomes, notably distress and despair, despite advanced disease. Results return to the clinic, allowing iterative update and evaluation. CONCLUSIONS: An ePRO-based rapid learning cancer clinic is feasible, providing real-time research-quality data to support comparative effectiveness research.

Authors
Abernethy, AP; Ahmad, A; Zafar, SY; Wheeler, JL; Reese, JB; Lyerly, HK
MLA Citation
Abernethy, AP, Ahmad, A, Zafar, SY, Wheeler, JL, Reese, JB, and Lyerly, HK. "Electronic patient-reported data capture as a foundation of rapid learning cancer care." Med Care 48.6 Suppl (June 2010): S32-S38.
PMID
20473201
Source
pubmed
Published In
Medical Care
Volume
48
Issue
6 Suppl
Publish Date
2010
Start Page
S32
End Page
S38
DOI
10.1097/MLR.0b013e3181db53a4

Use of gene expression signatures to predict in vivo sensitivity of human metastatic colorectal cancer to chemotherapy and to identify novel drug combinations.

Authors
VanDeusen, JB; Osada, T; Morse, M; Clary, BM; Lyerly, HK; Nevins, JR; Clay, TM; Febbo, PG; Hsu, SD
MLA Citation
VanDeusen, JB, Osada, T, Morse, M, Clary, BM, Lyerly, HK, Nevins, JR, Clay, TM, Febbo, PG, and Hsu, SD. "Use of gene expression signatures to predict in vivo sensitivity of human metastatic colorectal cancer to chemotherapy and to identify novel drug combinations." May 20, 2010.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Use of gene expression signatures to identify origin of primary and therapeutic strategies for patients with advanced solid tumors

Authors
Hsu, SD; Kim, MK; Foye, A; Silvestri, A; Lyerly, HK; Morse, M; III, PE; Febbo, PG
MLA Citation
Hsu, SD, Kim, MK, Foye, A, Silvestri, A, Lyerly, HK, Morse, M, III, PE, and Febbo, PG. "Use of gene expression signatures to identify origin of primary and therapeutic strategies for patients with advanced solid tumors." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Role of the type III TGF-b receptor in mediating immunosuppression during breast cancer progression

Authors
Hanks, BA; Lee, JD; Morse, M; Clay, TM; Lyerly, HK; Blobe, AC
MLA Citation
Hanks, BA, Lee, JD, Morse, M, Clay, TM, Lyerly, HK, and Blobe, AC. "Role of the type III TGF-b receptor in mediating immunosuppression during breast cancer progression." May 20, 2010.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Effect of a novel recombinant alphaviral vector on tolerance to self-antigen in the setting of elevated regulatory T cells.

Authors
Morse, M; Hobeika, A; Osada, T; Berglund, P; Negri, S; Niedzwiecki, D; Hubby, B; Burnett, B; Clay, TM; Lyerly, HK
MLA Citation
Morse, M, Hobeika, A, Osada, T, Berglund, P, Negri, S, Niedzwiecki, D, Hubby, B, Burnett, B, Clay, TM, and Lyerly, HK. "Effect of a novel recombinant alphaviral vector on tolerance to self-antigen in the setting of elevated regulatory T cells." May 20, 2010.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Identification of select glucocorticoids as Smoothened agonists: potential utility for regenerative medicine.

Regenerative medicine holds the promise of replacing damaged tissues largely by stem cell activation. Hedgehog signaling through the plasma membrane receptor Smoothened (Smo) is an important process for regulating stem cell proliferation. The development of Hedgehog-related therapies has been impeded by a lack of US Food and Drug Administration (FDA)-approved Smo agonists. Using a high-content screen with cells expressing Smo receptors and a beta-arrestin2-GFP reporter, we identified four FDA-approved drugs, halcinonide, fluticasone, clobetasol, and fluocinonide, as Smo agonists that activate Hedgehog signaling. These drugs demonstrated an ability to bind Smo, promote Smo internalization, activate Gli, and stimulate the proliferation of primary neuronal precursor cells alone and synergistically in the presence of Sonic Hedgehog protein. Halcinonide, fluticasone, clobetasol, and fluocinonide provide an unprecedented opportunity to develop unique clinical strategies to treat Hedgehog-dependent illnesses.

Authors
Wang, J; Lu, J; Bond, MC; Chen, M; Ren, X-R; Lyerly, HK; Barak, LS; Chen, W
MLA Citation
Wang, J, Lu, J, Bond, MC, Chen, M, Ren, X-R, Lyerly, HK, Barak, LS, and Chen, W. "Identification of select glucocorticoids as Smoothened agonists: potential utility for regenerative medicine." Proc Natl Acad Sci U S A 107.20 (May 18, 2010): 9323-9328.
PMID
20439738
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
107
Issue
20
Publish Date
2010
Start Page
9323
End Page
9328
DOI
10.1073/pnas.0910712107

X-linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ErbB1/2 tyrosine kinase inhibitor.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer that is often characterized by ErbB2 overexpression. ErbB2 targeting is clinically relevant using trastuzumab (anti-ErbB2 antibody) and lapatinib (small-molecule ErbB1/2 inhibitor). However, acquired resistance is a common outcome even in IBC patients who show an initial clinical response, which limits the efficacy of these agents. In the present study, using a clonal population of GW583340 (lapatinib analogue, ErbB1/2 inhibitor)-resistant IBC cells, we identified the overexpression of an antiapoptotic protein, X-linked inhibitor of apoptosis protein (XIAP), in acquired resistance to GW583340 in both ErbB2-overexpressing SUM190 and ErbB1-activated SUM149 cell lines derived from primary IBC tumors. A marked decrease in p-ErbB2, p-ErbB1, and downstream signaling was evident in the GW583340-resistant cells (rSUM190 and rSUM149) similar to parental counterparts treated with the drug, suggesting that the primary mechanism of action of GW583340 was not compromised in resistant cells. However, rSUM190 and rSUM149 cells growing in GW583340 had significant XIAP overexpression and resistance to GW583340-mediated apoptosis. Additionally, stable XIAP overexpression using a lentiviral system reversed sensitivity to GW583340 in parental cells. The observed overexpression was identified to be caused by IRES-mediated XIAP translation. XIAP downregulation in rSUM190 and rSUM149 cells using a small-molecule inhibitor (embelin), which abrogates the XIAP/procaspase-9 interaction, resulted in decreased viability, showing that XIAP is required for survival of cells with acquired resistance to GW583340. These studies establish the feasibility of development of an XIAP inhibitor that potentiates apoptosis for use in IBC patients with resistance to ErbB2-targeting agents.

Authors
Aird, KM; Ghanayem, RB; Peplinski, S; Lyerly, HK; Devi, GR
MLA Citation
Aird, KM, Ghanayem, RB, Peplinski, S, Lyerly, HK, and Devi, GR. "X-linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ErbB1/2 tyrosine kinase inhibitor." Mol Cancer Ther 9.5 (May 2010): 1432-1442.
PMID
20406946
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
9
Issue
5
Publish Date
2010
Start Page
1432
End Page
1442
DOI
10.1158/1535-7163.MCT-10-0160

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

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

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

The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling.

Wnt proteins bind to seven-transmembrane Frizzled receptors to mediate the important developmental, morphogenetic, and stem cell related tissue-regenerative effects of Wnt signaling. Dysregulated Wnt signaling is associated with many cancers. Currently, there are no drug candidates or even tool compounds that modulate Wnt-mediated receptor trafficking, and subsequent Wnt signaling. We examined libraries of FDA-approved drugs for their utility as Frizzled internalization modulators, employing a primary imaged-based GFP fluorescence assay that uses Frizzled1 endocytosis as the readout. We now report that the anti-helminthic niclosamide, a drug used for the treatment of tapeworm, promotes Frizzled1 endocytosis, downregulates Dishevelled-2 protein, and inhibits Wnt3A-stimulated beta-catenin stabilization and LEF/TCF reporter activity. Additionally, following niclosamide-mediated internalization, the Frizzled1 receptor colocalizes in vesicles containing transferrin and agonist-activated beta(2)-adrenergic receptor. Therefore, niclosamide may serve as a negative modulator of Wnt/Frizzled1 signaling by depleting upstream signaling molecules (i.e., Frizzled and Dishevelled) and moreover may provide a valuable means of studying the physiological consequences of Wnt signaling.

Authors
Chen, M; Wang, J; Lu, J; Bond, MC; Ren, X-R; Lyerly, HK; Barak, LS; Chen, W
MLA Citation
Chen, M, Wang, J, Lu, J, Bond, MC, Ren, X-R, Lyerly, HK, Barak, LS, and Chen, W. "The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling." Biochemistry 48.43 (November 3, 2009): 10267-10274.
PMID
19772353
Source
pubmed
Published In
Biochemistry
Volume
48
Issue
43
Publish Date
2009
Start Page
10267
End Page
10274
DOI
10.1021/bi9009677

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

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

MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition.

BACKGROUND: The X-linked inhibitor of apoptosis protein (XIAP), an endogenous apoptosis suppressor, can determine the level of caspase accumulation and the resultant response to apoptosis-inducing agents such as cisplatin in epithelial ovarian cancer (EOC). In addition, the mismatch repair protein, hMLH1, has been linked to DNA damage-induced apoptosis by cisplatin by both p53-dependent and -independent mechanisms. METHODS: In this study, hMLH1 expression was correlated with clinical response to platinum drugs and survival in advanced stage (III-IV) EOC patients. We then investigated whether MLH1 loss was a determinant in anti-apoptosis response to cisplatin mediated by XIAP in isogenic and established EOC cell lines with differential p53 status. RESULTS: The percentage of cells undergoing cisplatin-induced cell killing was higher in MLH1-proficient cells than in MLH1-defective cells. In addition, the presence of wild-type hMLH1 or hMLH1 re-expression significantly increased sensitivity to 6-thioguanine, a MMR-dependent agent. Cell-death response to 6-thioguanine and cisplatin was associated with significant proteolysis of MLH1, with XIAP destabilisation and increased caspase-3 activity. The siRNA-mediated inhibition of XIAP increased MLH1 proteolysis and cell death in MLH1-proficient cells but not in MLH1-defective cells. CONCLUSION: These data suggest that XIAP inhibitors may prove to be an effective means of sensitising EOC to MLH1-dependent apoptosis.

Authors
Ding, X; Mohd, AB; Huang, Z; Baba, T; Bernardini, MQ; Lyerly, HK; Berchuck, A; Murphy, SK; Buermeyer, AB; Devi, GR
MLA Citation
Ding, X, Mohd, AB, Huang, Z, Baba, T, Bernardini, MQ, Lyerly, HK, Berchuck, A, Murphy, SK, Buermeyer, AB, and Devi, GR. "MLH1 expression sensitises ovarian cancer cells to cell death mediated by XIAP inhibition." Br J Cancer 101.2 (July 21, 2009): 269-277.
PMID
19603033
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
2
Publish Date
2009
Start Page
269
End Page
277
DOI
10.1038/sj.bjc.6605180

Feasibility and acceptability to patients of a longitudinal system for evaluating cancer-related symptoms and quality of life: pilot study of an e/Tablet data-collection system in academic oncology.

Programmed, notebook-style, personal computers ("e/Tablets") can collect symptom and quality-of-life (QOL) data at the point of care. Patients use an e/Tablet in the clinic waiting area to complete electronic surveys. Information then travels wirelessly to a server, which generates a real-time report for use during the clinical visit. The objective of this study was to determine whether academic oncology patients find e/Tablets logistically acceptable and a satisfactory means of communicating symptoms to providers during repeated clinic visits. Sixty-six metastatic breast cancer patients at Duke Breast Cancer Clinic participated. E/Tablets were customized to electronically administer a satisfaction/acceptability survey, several validated questionnaires, and the Patient Care Monitor (PCM) review of symptoms survey. At each of the four visits within six months, participants completed the patient satisfaction/acceptability survey, which furnished data for the current analysis. Participant demographics were: mean age of 54 years, 77% Caucasian, and 47% with less than a college education. Participants reported that e/Tablets were easy to read (94%), easy to navigate (99%), and had a comfortable weight (90%); they found it easy to respond to questions using the e/Tablet (98%). Seventy-five percent initially indicated satisfaction with PCM for reporting symptoms; this proportion increased over time. By the last visit, 88% of participants indicated that they would recommend the PCM to other patients; 74% felt that the e/Tablet helped them remember symptoms to report to their clinician. E/Tablets offered a feasible and acceptable method for collecting longitudinal patient-reported symptom and QOL data within an academic, tertiary care, breast cancer clinic.

Authors
Abernethy, AP; Herndon, JE; Wheeler, JL; Day, JM; Hood, L; Patwardhan, M; Shaw, H; Lyerly, HK
MLA Citation
Abernethy, AP, Herndon, JE, Wheeler, JL, Day, JM, Hood, L, Patwardhan, M, Shaw, H, and Lyerly, HK. "Feasibility and acceptability to patients of a longitudinal system for evaluating cancer-related symptoms and quality of life: pilot study of an e/Tablet data-collection system in academic oncology." J Pain Symptom Manage 37.6 (June 2009): 1027-1038.
PMID
19394793
Source
pubmed
Published In
Journal of Pain and Symptom Management
Volume
37
Issue
6
Publish Date
2009
Start Page
1027
End Page
1038
DOI
10.1016/j.jpainsymman.2008.07.011

Impact of a psychosocial intervention on performance status and coping

Authors
Lyerly, HK; Staley, T; II, HJE; Coan, A; Wheeler, JL; Rowe, K; Horne, B; Abernethy, AP
MLA Citation
Lyerly, HK, Staley, T, II, HJE, Coan, A, Wheeler, JL, Rowe, K, Horne, B, and Abernethy, AP. "Impact of a psychosocial intervention on performance status and coping." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Electronic patient-reported data capture as the foundation of a learning health care system

Authors
Abernethy, AP; Zafar, SY; Coeytaux, R; Rowe, K; Wheeler, JL; Lyerly, HK
MLA Citation
Abernethy, AP, Zafar, SY, Coeytaux, R, Rowe, K, Wheeler, JL, and Lyerly, HK. "Electronic patient-reported data capture as the foundation of a learning health care system." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Impact of a psychosocial intervention on performance status and coping.

9611 Background: Psychosocial distress is a critical cancer comorbidity; new interventions are needed. Pathfinders, a manualized psychosocial care program, provides patient navigation, counseling, coping skills training, mind/body techniques, and lifestyle advice.This prospective, single-arm, pilot study enrolled adult metastatic breast cancer patients with prognosis ≥6 months. Consenting participants met with a Pathfinder (trained social worker) at least monthly, with interim phone/email contact. Pathfinders worked with patients to identify inner strengths, teach coping skills, engage complementary/alternative providers, employ mind/body techniques, and support healthy lifestyle. At baseline, month 3 and month 6, patients completed surveys including Patient Care Monitor (PCM; a review of systems with 6 subscales and a global quality of life [QOL] score), and Functional Assessment of Chronic Illness Therapy - Fatigue subscale (FACIT-F).Participants (n=50) were: mean age 51.2 years (SD 11.5); 24% non-white; 74% married; 50% did not complete college; the cohort had advanced cancer and short prognosis with 6-month attrition from death, 18%. Scores on the PCM Distress subscale improved from baseline to 3 months with a mean change of -3.42 (n=36; p=0.008) and from baseline to 6 months of -4.11 (n=28; p=0.002). PCM Despair subscale scores also improved: mean change of -4.53 (p=0.006) and -6.93 (p=0.016), respectively. PCM QOL and FACIT-F scores improved from baseline to 3 months; however, the change at 6 months, with smaller sample, was not statistically significant. Mean change in QOL from baseline to 3 and 6 months was 2.88 (n=30; p=0.006) and 2.66 (n=25; p=0.079), respectively. Mean change in FACIT-F from baseline to 3 and 6 months was 2.91 (n=39; p=0.020) and 1.29 (n=32; p=0.407), respectively.Pathfinders had significant positive effect on key psychosocial and QOL outcomes, notably distress and despair, for cancer patients despite advanced disease and worsening symptoms. No significant financial relationships to disclose.

Authors
Lyerly, HK; Staley, T; Herndon, JE; Coan, A; Wheeler, JL; Rowe, K; Horne, B; Abernethy, AP
MLA Citation
Lyerly, HK, Staley, T, Herndon, JE, Coan, A, Wheeler, JL, Rowe, K, Horne, B, and Abernethy, AP. "Impact of a psychosocial intervention on performance status and coping." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 9611-.
PMID
27963859
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
9611

Electronic patient-reported data capture as the foundation of a learning health care system.

6522 Background: In a "learning healthcare system" clinical decisions are supported by accurate information delivered at point of care; information gathered today iteratively informs future care and research.Customized software on wireless tablet personal computers presented a review of systems (ROS) instrument, validated research surveys (e.g., quality of life [QOL]), and a satisfaction survey, tailored by user. The system was piloted in the Duke Cancer Clinics and affiliated hospitals. We previously demonstrated equivalence of electronic and paper survey data. We conducted a series of studies using similar procedures to evaluate feasibility, acceptability, and utility.First, we assessed the ability to collect ROS data at point of care to inform the clinic visit for participating breast (n = 65), gastrointestinal (n = 113), and lung (n = 97) cancer patients. Duke physicians reported that the system's clinical reports informed care and increased dictation efficiency. Second, we assessed patient satisfaction in the breast cancer cohort. Participants found the computers easy to read (94%), navigate (99%), and use (98%); the system helped 74% remember forgotten concerns to report to their clinician. Third, we assessed whether these data could contribute to current research. If the patient was on another clinical trial, PRO data (e.g., pain, QOL) were delivered to the investigator for research purposes in real time; data governance rules provided assurance to investigators. Fourth, we identified whether the PRO data could inform future research directions. Symptoms monitored longitudinally in aggregate uncovered unmet needs. Sexual distress was an underserved concern; intervention studies were initiated. Warehoused PRO data were integrated with clinical trials, genomic, biomarker, radiology, and administrative datasets for analyses. The approach has been scaled to 4 clinics and 3 hospitals.An integrated, real-time, electronic data capture system that interdigitates PROs with clinical and other data allows creation of a learning oncology environment that continuously improves care and research. Advantages include: patient-centeredness, description of the PRO phenotype, interoperability, and interface with caBIG infrastructure. No significant financial relationships to disclose.

Authors
Abernethy, AP; Zafar, SY; Coeytaux, R; Rowe, K; Wheeler, JL; Lyerly, HK
MLA Citation
Abernethy, AP, Zafar, SY, Coeytaux, R, Rowe, K, Wheeler, JL, and Lyerly, HK. "Electronic patient-reported data capture as the foundation of a learning health care system." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 6522-.
PMID
27964028
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
6522

Use of tablet personal computers for sensitive patient-reported information.

Notebook-style computers (e/Tablets) are increasingly replacing paper methods for collecting patient-reported information. Discrepancies in data between these methods have been found in oncology for sexuality-related questions. A study was performed to formulate hypotheses regarding causes for discrepant responses and to analyze whether electronic data collection adds value over paper-based methods when collecting data on sensitive topics. A total of 56 breast cancer patients visiting Duke Breast Clinic (North Carolina) participated by responding to 12 subscales of 5 survey instruments in electronic (e/Tablet) format and to a paper version of 1 of these surveys, at each visit. Twenty-one participants (38%) provided dissimilar responses on paper and electronic surveys to one item of the Functional Assessment of Cancer Therapy-General (FACT-G) Social Well-Being scale that asked patients to rate their satisfaction with their current sex life. Among these 21 patients were 8 patients who answered the question in the electronic environment, and 13 patients who answered both paper and electronic versions but with different responses. Eleven patients (29%) did not respond to the item on either e/Tablet or paper; 45 patients (80%) answered it on e/Tablet; and 37 patients (66%) responded on the paper version. The e/Tablet electronic system may provide a "safer" environment than paper questionnaires for cancer patients to answer private or highly personal questions on sensitive topics such as sexuality.

Authors
Dupont, A; Wheeler, J; Herndon, JE; Coan, A; Zafar, SY; Hood, L; Patwardhan, M; Shaw, HS; Lyerly, HK; Abernethy, AP
MLA Citation
Dupont, A, Wheeler, J, Herndon, JE, Coan, A, Zafar, SY, Hood, L, Patwardhan, M, Shaw, HS, Lyerly, HK, and Abernethy, AP. "Use of tablet personal computers for sensitive patient-reported information." J Support Oncol 7.3 (May 2009): 91-97.
PMID
19507456
Source
pubmed
Published In
The Journal of Supportive Oncology
Volume
7
Issue
3
Publish Date
2009
Start Page
91
End Page
97

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

Antibody-based immunotherapy: targeting CSPG4 on human basal breast cancer stem cells

Authors
Wang, X; Osada, T; Wang, Y; Miyazato, P; Thorne, S; DeLeo, A; Lyerly, HK; Clay, T; Ferrone, S
MLA Citation
Wang, X, Osada, T, Wang, Y, Miyazato, P, Thorne, S, DeLeo, A, Lyerly, HK, Clay, T, and Ferrone, S. "Antibody-based immunotherapy: targeting CSPG4 on human basal breast cancer stem cells." January 15, 2009.
Source
wos-lite
Published In
Cancer Research
Volume
69
Issue
2
Publish Date
2009
Start Page
314S
End Page
315S

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

Improving health care efficiency and quality using tablet personal computers to collect research-quality, patient-reported data.

OBJECTIVE: To determine whether e/Tablets (wireless tablet computers used in community oncology clinics to collect review of systems information at point of care) are feasible, acceptable, and valid for collecting research-quality data in academic oncology. DATA/SETTING: Primary/Duke Breast Cancer Clinic. DESIGN: Pilot study enrolling sample of 66 breast cancer patients. METHODS: Data were collected using paper- and e/Tablet-based surveys: Functional Assessment of Cancer Therapy General, Functional Assessment of Cancer Therapy-Breast, MD Anderson Symptom Inventory, Functional Assessment of Chronic Illness Therapy (FACIT), Self-Efficacy; and two questionnaires: feasibility, satisfaction. PRINCIPAL FINDINGS: Patients supported e/Tablets as: easy to read (94 percent), easy to respond to (98 percent), comfortable weight (87 percent). Generally, electronic responses validly reflected responses provided by standard paper data collection on nearly all subscales tested. CONCLUSIONS: e/Tablets offer a valid, feasible, acceptable method for collecting research-quality, patient-reported outcomes data in outpatient academic oncology.

Authors
Abernethy, AP; Herndon, JE; Wheeler, JL; Patwardhan, M; Shaw, H; Lyerly, HK; Weinfurt, K
MLA Citation
Abernethy, AP, Herndon, JE, Wheeler, JL, Patwardhan, M, Shaw, H, Lyerly, HK, and Weinfurt, K. "Improving health care efficiency and quality using tablet personal computers to collect research-quality, patient-reported data." Health Serv Res 43.6 (December 2008): 1975-1991.
PMID
18761678
Source
pubmed
Published In
Health Services Research
Volume
43
Issue
6
Publish Date
2008
Start Page
1975
End Page
1991
DOI
10.1111/j.1475-6773.2008.00887.x

Translational Research Working Group developmental pathway for immune response modifiers.

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the investment of National Cancer Institute in translational research and envision its future. The Translational Research Working Group conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of immune response modifiers such as vaccines and cytokines. A hallmark of the Immune Response Modifier Developmental Pathway is the coordinated development of multiple components. The Immune Response Modifier Pathway was conceived not as a comprehensive description of the corresponding real-world processes but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper discusses key challenges associated with the immune response modifier agent development process in light of the pathway.

Authors
Cheever, MA; Schlom, J; Weiner, LM; Lyerly, HK; Disis, ML; Greenwood, A; Grad, O; Nelson, WG; Translational Research Working Group,
MLA Citation
Cheever, MA, Schlom, J, Weiner, LM, Lyerly, HK, Disis, ML, Greenwood, A, Grad, O, Nelson, WG, and Translational Research Working Group, . "Translational Research Working Group developmental pathway for immune response modifiers." Clin Cancer Res 14.18 (September 15, 2008): 5692-5699.
PMID
18794077
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
18
Publish Date
2008
Start Page
5692
End Page
5699
DOI
10.1158/1078-0432.CCR-08-1266

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

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

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

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

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

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

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

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

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

Targeting hedgehog signaling in medulloblastoma

Authors
Wang, J; Liu, R; Bond, M; Chen, M; Singh, S; Ali-Osman, F; Lefkowitz, RJ; Diehl, AM; Lyerly, HK; Barak, L; Chen, W
MLA Citation
Wang, J, Liu, R, Bond, M, Chen, M, Singh, S, Ali-Osman, F, Lefkowitz, RJ, Diehl, AM, Lyerly, HK, Barak, L, and Chen, W. "Targeting hedgehog signaling in medulloblastoma." October 2007.
Source
wos-lite
Published In
Neuro-Oncology
Volume
9
Issue
4
Publish Date
2007
Start Page
560
End Page
561

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

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

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

Adenovirus-human HER2 vaccine inhibits breast cancer growth and vaccine induced antibodies (VIA) are efficacious against Herceptin-refractory human breast cancer

Authors
Wei, J; Hartman, Z; Osada, T; Yang, XY; Lei, G; Jiang, H; Chong, G; Amalfitano, A; Lyerly, HK; Morse, M; Clay, T
MLA Citation
Wei, J, Hartman, Z, Osada, T, Yang, XY, Lei, G, Jiang, H, Chong, G, Amalfitano, A, Lyerly, HK, Morse, M, and Clay, T. "Adenovirus-human HER2 vaccine inhibits breast cancer growth and vaccine induced antibodies (VIA) are efficacious against Herceptin-refractory human breast cancer." JOURNAL OF IMMUNOLOGY 178 (April 1, 2007).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Publish Date
2007

A New Human Adenoviral Type 4 viral vector system displays highly enhanced immunogenicity that is complement-dependent and correlates with altered adaptive responses

Authors
Hartman, Z; Appledorn, D; Mendelson, T; Lyerly, HK; Clay, T; Amalfitano, A
MLA Citation
Hartman, Z, Appledorn, D, Mendelson, T, Lyerly, HK, Clay, T, and Amalfitano, A. "A New Human Adenoviral Type 4 viral vector system displays highly enhanced immunogenicity that is complement-dependent and correlates with altered adaptive responses." JOURNAL OF IMMUNOLOGY 178 (April 1, 2007).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Publish Date
2007

Modulation of adenoviral vector immune responses through the over-expression of immune adaptor and viral immuno-modulatory genes

Authors
Hartman, Z; Yang, XY; Lei, G; Amalfitano, A; Morse, M; Lyerly, HK; Clay, T
MLA Citation
Hartman, Z, Yang, XY, Lei, G, Amalfitano, A, Morse, M, Lyerly, HK, and Clay, T. "Modulation of adenoviral vector immune responses through the over-expression of immune adaptor and viral immuno-modulatory genes." JOURNAL OF IMMUNOLOGY 178 (April 1, 2007).
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
178
Publish Date
2007

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

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

Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood

NKT cells are important for initiating and regulating immune responses. We investigated the age-related changes in the CD1d-restricted semi-invariant NKT (iNKT) cells in peripheral blood of healthy adults. The iNKT cell frequency was 2.5- to 10.7-fold less in healthy elderly subjects (61 years and over) compared to the healthy young subjects (20-40 years, p < 0.001). This age-related decline in iNKT cells was observed both in freshly isolated PBMC and in cultures where iNKT cells were enriched by α-GalCer stimulation using either the Vα24/Vβ11 TCR antibody pair or the CD1d-tetramer as the iNKT cell marker. The decline in frequency was associated with an alteration in the iNKT cell subset compositions: an increase in the proportion of CD4+ subset and a decrease in the proportion of CD4/CD8 double-negative (DN) subset. The age-related decline in iNKT cells and changes in subset composition were independent from the age-related changes of conventional T cells/T cell subsets. Additionally, there was a Th1 to Th2 shift in the cytokine response profile from iNKT cells with aging. We conclude that aging is associated with a significant decline in iNKT cell frequency in peripheral blood, accompanied with alterations in subset composition and cytokine response profile. © 2007 Elsevier Inc. All rights reserved.

Authors
Jing, Y; Gravenstein, S; Chaganty, NR; Chen, N; Lyerly, KH; Joyce, S; Deng, Y
MLA Citation
Jing, Y, Gravenstein, S, Chaganty, NR, Chen, N, Lyerly, KH, Joyce, S, and Deng, Y. "Aging is associated with a rapid decline in frequency, alterations in subset composition, and enhanced Th2 response in CD1d-restricted NKT cells from human peripheral blood." Experimental Gerontology 42.8 (2007): 719-732.
PMID
17368996
Source
scival
Published In
Experimental Gerontology
Volume
42
Issue
8
Publish Date
2007
Start Page
719
End Page
732
DOI
10.1016/j.exger.2007.01.009

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

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

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

Maximizing the retention of antigen specific lymphocyte function after cryopreservation

The ability to cryopreserve lymphocytes in peripheral blood mononuclear cells (PBMC) to retain their function after thawing is critical to the analysis of cancer immunotherapy studies. We evaluated a variety of cryopreservation strategies with the aim of developing an optimized protocol for freezing and thawing PBMC to retain viability and function. We determined several factors which do not affect cell viability after cryopreservation such as shipping frozen samples on dry ice, the length of time and speed at which samples are washed and centrifuged after thawing, and the number of cells frozen per container. Different media additives, however, did impact the viability of the cells after thawing. There was a significant reduction in the viability of the cells after freezing when using human AB serum compared to all other additives tested (p < 0.000). A second critical parameter was the temperature of the media used to wash the cells after removal from the cryotubes. When the media was cooled to 4°C prior to washing, the mean viability was 69.7 ± 12.5%, at 25°C 92.55 ± 3.1%, and at 37°C 95.11 ± 2.5%. Finally, we used an optimized cryopreservation protocol with different media additives to determine if functional T cell responses to tetanus toxoid could be preserved. There was a statistically significant correlation between the tetanus specific stimulation index (S.I.) of the non-cryopreserved PBMC and SI obtained from cells frozen with media containing human serum albumin as compared to other additives such as dextran or fetal bovine serum. © 2005 Elsevier B.V. All rights reserved.

Authors
Disis, ML; Rosa, CD; Goodell, V; Kuan, L-Y; Chang, JCC; Kuus-Reichel, K; Clay, TM; Lyerly, HK; Bhatia, S; Ghanekar, SA; Maino, VC; Maecker, HT
MLA Citation
Disis, ML, Rosa, CD, Goodell, V, Kuan, L-Y, Chang, JCC, Kuus-Reichel, K, Clay, TM, Lyerly, HK, Bhatia, S, Ghanekar, SA, Maino, VC, and Maecker, HT. "Maximizing the retention of antigen specific lymphocyte function after cryopreservation." Journal of Immunological Methods 308.1-2 (2006): 13-18.
PMID
16337957
Source
scival
Published In
Journal of Immunological Methods
Volume
308
Issue
1-2
Publish Date
2006
Start Page
13
End Page
18
DOI
10.1016/j.jim.2005.09.011

Global role of the immune system in identifying cancer initiation and limiting disease progression.

Authors
Disis, ML; Lyerly, HK
MLA Citation
Disis, ML, and Lyerly, HK. "Global role of the immune system in identifying cancer initiation and limiting disease progression." J Clin Oncol 23.35 (December 10, 2005): 8923-8925.
PMID
16339754
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
35
Publish Date
2005
Start Page
8923
End Page
8925
DOI
10.1200/JCO.2005.10.007

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

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

Correlation of clinical outcome with natural killer (NK) response to an anti-cancer, dendritic cell-based vaccine.

Authors
Morse, M; Osada, T; Hobeika, A; Chui, S; Clay, T; Lyerly, HK
MLA Citation
Morse, M, Osada, T, Hobeika, A, Chui, S, Clay, T, and Lyerly, HK. "Correlation of clinical outcome with natural killer (NK) response to an anti-cancer, dendritic cell-based vaccine." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
187S
End Page
187S

Correlation of clinical outcome with natural killer (NK) response to an anti-cancer, dendritic cell-based vaccine.

2585 Background: Cancer vaccines have generally been developed to activate antigen-specific T cell responses, but few studies have attempted to evaluate the non-specific, yet potentially clinically-relevant, NK response to immunization. We hypothesized that the NK response would predict clinical benefit in immunized patients.In a phase I clinical trial of a vaccine consisting of autologous dendritic cell (DC) loaded with a fowlpox vector encoding CEA (rF-CEA(6D)-TRICOM, we measured CEA-specific immune responses by ELISPOT assay and reported increases in 12/14 patients (Proc ASCO2004, abst 2508). Using archived peripheral blood specimens (n=9) from before and after all immunizations, we measured CD3-CD56+ NK% and NK cytolytic activity against the NK target K562. These data were compared with the clinical outcome of the patients.There were no differences in the percentage of NK cells or NK markers NKG2A, NKG2C, NKG2D before or after immunization. In contrast, NK cytolytic activity increased in 4 patients (range 2.5 to 5 times greater lytic activity), was stable in 2 and decreased in 3. When patients were grouped by clinical activity (stable disease/no evidence of disease (n=5) versus progressive disease (N=4) at three months), we observed that the majority of those with stable disease/no evidence of disease had increases in their NK activity (Chi Square, P= 0.0163). The NK results predicted more closely the clinical outcome than did T cell responses (Chi Square, P=NS).NK responses following immunization with a dendritic cell vaccine are associated with clinical benefit as indicated by a lack of progressive disease. Monitoring of NK response during vaccine studies should be routinely performed. No significant financial relationships to disclose.

Authors
Morse, M; Osada, T; Hobeika, A; Chui, S; Clay, T; Lyerly, HK
MLA Citation
Morse, M, Osada, T, Hobeika, A, Chui, S, Clay, T, and Lyerly, HK. "Correlation of clinical outcome with natural killer (NK) response to an anti-cancer, dendritic cell-based vaccine." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23.16_suppl (June 2005): 2585-.
PMID
27945884
Source
epmc
Published In
Journal of Clinical Oncology
Volume
23
Issue
16_suppl
Publish Date
2005
Start Page
2585

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

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, DH; Le Pecq, JB; 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, DH, Le Pecq, JB, and Lyerly, HK. "A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer." Journal of translational medicine [electronic resource]. 3.1 (February 2005): 9-. (Academic Article)
PMID
15723705
Source
manual
Published In
Journal of Translational Medicine
Volume
3
Issue
1
Publish Date
2005
Start Page
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

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-

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

Your Ad here: optimizing adenoviral vector-based vaccines

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Your Ad here: optimizing adenoviral vector-based vaccines." Blood 104.9 (November 1, 2004): 2612-2613.
Source
crossref
Published In
Blood
Volume
104
Issue
9
Publish Date
2004
Start Page
2612
End Page
2613
DOI
10.1182/blood-2004-08-3082

Effect of Cryopreservation on Assays of Antigen-Specific T Cells: Comparison of Tetramer, Cytokine Flow Cytometry, and ELISPOT

Authors
Maecker, H; Moon, J; Byhatia, S; Ghanekar, S; Maino, V; Kuus-Reichel, T; Summers, A; Clay, T; Lyerly, H; DelaRosa, C; Ankerst, D; Disis, M
MLA Citation
Maecker, H, Moon, J, Byhatia, S, Ghanekar, S, Maino, V, Kuus-Reichel, T, Summers, A, Clay, T, Lyerly, H, DelaRosa, C, Ankerst, D, and Disis, M. "Effect of Cryopreservation on Assays of Antigen-Specific T Cells: Comparison of Tetramer, Cytokine Flow Cytometry, and ELISPOT." November 2004.
Source
crossref
Published In
Journal of Immunotherapy
Volume
27
Issue
6
Publish Date
2004
Start Page
S42
End Page
S42
DOI
10.1097/00002371-200411000-00153

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

Safety profile of therapeutic pox virus-based vaccines for cancer.

Authors
Kaufman, HL; Dipaola, R; Von Mehren, M; Marshall, J; Lyerly, HK; Streicher, H; Schlom, J; Panicali, D; Schuetz, T
MLA Citation
Kaufman, HL, Dipaola, R, Von Mehren, M, Marshall, J, Lyerly, HK, Streicher, H, Schlom, J, Panicali, D, and Schuetz, T. "Safety profile of therapeutic pox virus-based vaccines for cancer." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
166S
End Page
166S

Phase I study of immunization with dendritic cells (DC) modified with recombinant fowlpox encoding carcinoembryonic antigen (CEA) and the triad of costimulatory molecules CD54, CD58, and CD80 (rF-CEA(6D)-TRICOM) in patients with advanced malignancies.

Authors
Morse, M; Clay, T; Hobeika, A; Osada, T; Panicali, D; Lyerly, HK
MLA Citation
Morse, M, Clay, T, Hobeika, A, Osada, T, Panicali, D, and Lyerly, HK. "Phase I study of immunization with dendritic cells (DC) modified with recombinant fowlpox encoding carcinoembryonic antigen (CEA) and the triad of costimulatory molecules CD54, CD58, and CD80 (rF-CEA(6D)-TRICOM) in patients with advanced malignancies." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
165S
End Page
165S

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

Safety profile of therapeutic pox virus-based vaccines for cancer.

2513 Background: The eradication of smallpox is, in part, attributed to the effectiveness of vaccination with poxvirus vaccines. Recombinant poxviruses have now been developed as core components of therapeutic tumor vaccines. To date >700 patients received a variety of anti-tumor poxvirus vaccines in clinical trials. A major objective of these early trials was a safety assessment and this study summarizes the safety profile of the Poxvirus Tumor Vaccine Initiative.The OBA, local IRB and biosafety committees approved all trials. Case report forms or medical records for all patients treated on recombinant poxvirus clinical trials through the NCI or Therion Biologics Corporation between 1991 and 2003 were reviewed.There were 707 patients treated in 29 clinical trials for a variety of tumors.. Vaccines consisted of vaccinia virus, fowlpox virus and ALVAC at doses between 106 - 109 pfu. Vaccines targeted CEA, PSA, MUC-1, gp100, MART-1, and tyrosinase. Second generation vaccines included B7.1 or TRICOM (B7.1, ICAM-1, and LFA-3) and some patients received GM-CSF and/or IL-2. Vaccines were administered through i.d., s.c., i.m., i.t., and i.v. routes. There were no deaths attributed to vaccination in the 707 evaluable patients and therapy was generally well tolerated. The most common adverse events reported were cutaneous reactions associated with local administration of the vaccines. In addition, mild systemic symptoms, such as fatigue, low grade fever, and malaise, were observed. There were 7 cases of serious events (SAEs) attributed to the vaccine following intravenous administration: 5 hypotension, 1 rash, and 1 fever/chills.Therapeutic vaccination with pox virus-based vectors has been tested in clinical trials including >700 patients over the past 10 years. The vaccines are well tolerated at a broad range of doses, routes of administration, tumor types, and regimens with only 7 SAEs after intravenous administration. These data demonstrate the safety profile of recombinant poxvirus vaccines and support the development of randomized trials evaluating clinical effectiveness for poxvirus vaccines in patients with cancer. [Table: see text].

Authors
Kaufman, HL; Dipaola, R; Von Mehren, M; Marshall, J; Lyerly, HK; Streicher, H; Schlom, J; Panicali, D; Schuetz, T
MLA Citation
Kaufman, HL, Dipaola, R, Von Mehren, M, Marshall, J, Lyerly, HK, Streicher, H, Schlom, J, Panicali, D, and Schuetz, T. "Safety profile of therapeutic pox virus-based vaccines for cancer." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 2513-.
PMID
28015029
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
2513

Phase I study of immunization with dendritic cells (DC) modified with recombinant fowlpox encoding carcinoembryonic antigen (CEA) and the triad of costimulatory molecules CD54, CD58, and CD80 (rF-CEA(6D)-TRICOM) in patients with advanced malignancies.

2508 Background: We hypothesize that the activity of vaccines based on DC loaded with tumor antigens will be enhanced by modifications that increase antigen expression and costimulatory activity of the DC.In an ongoing phase I study, we are administering 1, 2, or 3 cycles of 4 triweekly subcutaneous / intradermal injections of ex vivo generated DC (5 x 10E6 cells) modified with the recombinant fowlpox vector rF-CEA(6D)-TRICOM (2.5 x 10E7 pfu/5 x 10E7 DC).Thus far, 14 patients have been enrolled into the first 2 cohorts. 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 supraclavicular adenopathy that occurred several months after completion of the immunizations. Three other patients were stable through at least 1 cycle of immunization (3 months). Direct analysis of T cells in peripheral blood using the ELISpot assay demonstrated an increase in the frequency of T cells specific for the CEA-expressing vector in 10 of the 12 patients completing participation (range 10 to 541 CEA-specific cells/100,000 peripheral blood mononuclear cells (PBMC).) A greater CEA-specific response was observed for patients with either a minor response or stable disease following at least 1 cycle of therapy compared with those who progressed (mean of 241 vs 50 CEA-specific cells/100,000 PBMC, P=0.03). Cytokine flow cytometry demonstrated that the CEA-specific immune response occurred amongst both CD4 and CD8+ T cells in all responders. Changes in the frequency of CD4+CD25+ regulatory T cells were observed and, in some patients, were inversely correlated with the frequency of CEA-specific CD4+ T cells suggesting that regulatory mechanisms might impact the greatest magnitude of CEA-specific T cells that can be achieved.This immunization strategy is safe and feasible and activates potent CEA-specific immune responses. This study will continue into the third cohort. [Table: see text].

Authors
Morse, M; Clay, T; Hobeika, A; Osada, T; Panicali, D; Lyerly, HK
MLA Citation
Morse, M, Clay, T, Hobeika, A, Osada, T, Panicali, D, and Lyerly, HK. "Phase I study of immunization with dendritic cells (DC) modified with recombinant fowlpox encoding carcinoembryonic antigen (CEA) and the triad of costimulatory molecules CD54, CD58, and CD80 (rF-CEA(6D)-TRICOM) in patients with advanced malignancies." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 2508-.
PMID
28014999
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
2508

Accelerated partial breast irradiation after conservative surgery for breast cancer.

OBJECTIVE: To critically review the theoretical and actual risks and benefits of accelerated partial breast irradiation (APBI) after breast-conserving surgery. SUMMARY BACKGROUND DATA: Because of rapid evolution of radiation therapy techniques related to brachytherapy and three-dimensional conformal radiation therapy, APBI has very recently come to the forefront as a potential local treatment option for women with breast cancer. This review aims to give an overview of the biologic rationale for APBI techniques, and benefits and limitations of APBI techniques. METHODS: The authors reviewed the currently available published world medical literature on breast-conserving surgery with and without postoperative irradiation; all studies involving partial breast irradiation, including brachytherapy, for breast cancer; and currently accruing and planned APBI trials. The focus of this review was the early results of treatment in terms of toxicity, complications, cosmesis, and local control. RESULTS: On average, approximately 3% of patients treated with breast-conserving surgery will have an in-breast local recurrence away from the original lumpectomy site with or without postoperative standard whole-breast irradiation. The results of phase I-II studies involving approximately 500 patients treated with APBI after breast-conserving surgery have been published. Although many of the studies have limited long-term follow-up and potential selection bias, early results suggest that toxicity, cosmesis, and local control are comparable to outcomes seen after breast-conserving surgery followed by standard whole-breast irradiation. CONCLUSIONS: Recent advances in radiation delivery and published series of partial breast irradiation support large randomized trials comparing APBI with standard whole-breast irradiation after breast-conserving surgery.

Authors
Kuerer, HM; Julian, TB; Strom, EA; Lyerly, HK; Giuliano, AE; Mamounas, EP; Vicini, FA
MLA Citation
Kuerer, HM, Julian, TB, Strom, EA, Lyerly, HK, Giuliano, AE, Mamounas, EP, and Vicini, FA. "Accelerated partial breast irradiation after conservative surgery for breast cancer." Ann Surg 239.3 (March 2004): 338-351. (Review)
PMID
15075650
Source
pubmed
Published In
Annals of Surgery
Volume
239
Issue
3
Publish Date
2004
Start Page
338
End Page
351

Handbook of Cancer Vaccines

Michael A. Morse, Timothy M. Clay, H. Kim Lyerly. cellular vaccines poses new issues for the Food and Drug Administration and other regulators. Regulatory requirements for cellbased vaccines are discussed in Chapter 37.

Authors
Morse, MA; Clay, TM; Lyerly, HK
MLA Citation
Morse, MA, Clay, TM, and Lyerly, HK. Handbook of Cancer Vaccines. Springer Science & Business Media, January 1, 2004.
Source
google-books
Publish Date
2004

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

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

Thoracic paravertebral blockade for ambulatory breast cancer surgery

Authors
Nielsen, KC; Steele, SM; Pietrobon, R; Tucker, MS; Klein, SM; Lyerly, HK
MLA Citation
Nielsen, KC, Steele, SM, Pietrobon, R, Tucker, MS, Klein, SM, and Lyerly, HK. "Thoracic paravertebral blockade for ambulatory breast cancer surgery." 2004.
Source
wos-lite
Published In
Breast Cancer Research and Treatment
Volume
88
Publish Date
2004
Start Page
S135
End Page
S136

Maximizing the retention of antigen specific lymphocyte function after cryopreservation.

Authors
Disis, ML; dela Rosa, C; Goodell, V; Kuan, L; Chang, JCC; Kuus-Reichel, K; Clay, T; Lyerly, HK; Waters, CA; Ghanekar, SA; Maino, VC
MLA Citation
Disis, ML, dela Rosa, C, Goodell, V, Kuan, L, Chang, JCC, Kuus-Reichel, K, Clay, T, Lyerly, HK, Waters, CA, Ghanekar, SA, and Maino, VC. "Maximizing the retention of antigen specific lymphocyte function after cryopreservation." 2004.
Source
wos-lite
Published In
Journal of Immunotherapy
Volume
27
Issue
6
Publish Date
2004
Start Page
S40
End Page
S40
DOI
10.1097/00002371-200411000-00145

Magnitude and duration of antigen-specific immune response may affect clinical response

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Magnitude and duration of antigen-specific immune response may affect clinical response." December 1, 2003.
Source
scopus
Published In
Cancer Immunology, Immunotherapy
Volume
52
Issue
SUPPL. 1
Publish Date
2003

Tackling T-cell tumors

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Tackling T-cell tumors." BLOOD 102.7 (October 1, 2003): 2313-2313.
Source
wos-lite
Published In
Blood
Volume
102
Issue
7
Publish Date
2003
Start Page
2313
End Page
2313
DOI
10.1182/blood-2003-07-2579

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

Quantitating cellular immune responses to cancer vaccines.

While the future of immunotherapy in the treatment of cancer is promising, it is difficult to compare the various approaches because monitoring assays have not been standardized in approach or technique. Common assays for measuring the immune response need to be established so that these assays can one day serve as surrogate markers for clinical response. Assays that accurately detect and quantitate T-cell-mediated, antigen-specific immune responses are particularly desired. However, to date, increases in the number of cytotoxic T cells through immunization have not been correlated with clinical tumor regression. Ideally, then, a T-cell assay not only needs to be sensitive, specific, reliable, reproducible, simple, and quick to perform, it must also demonstrate close correlation with clinical outcome. Assays currently used to measure T-cell response are delayed-type hypersensitivity testing, flow cytometry using peptide major histocompatibility complex tetramers, lymphoproliferation assay, enzyme-linked immunosorbant assay, enzyme-linked immunospot assay, cytokine flow cytometry, direct cytotoxicity assay, measurement of cytokine mRNA by quantitative reverse transcriptase polymerase chain reaction, and limiting dilution analysis. The purpose of this review is to describe the attributes of each test and compare their advantages and disadvantages.

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Quantitating cellular immune responses to cancer vaccines." Semin Oncol 30.3 Suppl 8 (June 2003): 9-16. (Review)
PMID
12881807
Source
pubmed
Published In
Seminars in Oncology
Volume
30
Issue
3 Suppl 8
Publish Date
2003
Start Page
9
End Page
16

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

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

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

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

Mannose receptor antibody-mediated antigen presentation by human dendritic cells elicits HLA-restricted antigen-specific anti-tumor immunity

Authors
Ramakrishna, V; He, LZ; Treml, J; Connolly, J; Wang, XT; Smith, P; Vitale, L; O'Neill, T; Jones, C; Fanger, M; Morse, M; Clay, T; Lyerly, H; Endres, M; Keler, T
MLA Citation
Ramakrishna, V, He, LZ, Treml, J, Connolly, J, Wang, XT, Smith, P, Vitale, L, O'Neill, T, Jones, C, Fanger, M, Morse, M, Clay, T, Lyerly, H, Endres, M, and Keler, T. "Mannose receptor antibody-mediated antigen presentation by human dendritic cells elicits HLA-restricted antigen-specific anti-tumor immunity." 2003.
Source
wos-lite
Published In
Journal of Immunotherapy
Volume
26
Issue
6
Publish Date
2003
Start Page
S12
End Page
S12

Disparities in breast carcinoma treatment in Asian/Pacific Islander women. A challenge to the provider.

Authors
Chui, SY; Lyerly, HK
MLA Citation
Chui, SY, and Lyerly, HK. "Disparities in breast carcinoma treatment in Asian/Pacific Islander women. A challenge to the provider." Cancer 95.11 (December 1, 2002): 2257-2259.
PMID
12436429
Source
pubmed
Published In
Cancer
Volume
95
Issue
11
Publish Date
2002
Start Page
2257
End Page
2259
DOI
10.1002/cncr.10964

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

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

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

Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy.

The Society for Biological Therapy held a Workshop last fall devoted to immune monitoring for cancer immunotherapy trials. Participants included members of the academic and pharmaceutical communities as well as the National Cancer Institute and the Food and Drug Administration. Discussion focused on the relative merits and appropriate use of various immune monitoring tools. Six breakout groups dealt with assays of T-cell function, serologic and proliferation assays to assess B cell and T helper cell activity, and enzyme-linked immunospot assay, tetramer, cytokine flow cytometry, and reverse transcription polymerase chain reaction assays of T-cell immunity. General conclusions included: (1) future vaccine studies should be designed to determine whether T-cell dysfunction (tumor-specific and nonspecific) correlated with clinical outcome; (2) tetramer-based assays yield quantitative but not functional data (3) enzyme-linked immunospot assays have the lowest limit of detection (4) cytokine flow cytometry have a higher limit of detection than enzyme-linked immunospot assay, but offer the advantages of speed and the ability to identify subsets of reactive cells; (5) antibody tests are simple and accurate and should be incorporated to a greater extent in monitoring plans; (6) proliferation assays are imprecise and should not be emphasized in future studies; (7) the reverse transcription polymerase chain reaction assay is a promising research approach that is not ready for widespread application; and (8)there is a critical need to validate these assays as surrogates for vaccine potency and clinical effect. Current data and opinion support the use of a functional assay like the enzyme-linked immunospot assay or cytokine flow cytometry in combination with a quantitative assay like tetramers for immune monitoring. At present, assays appear to be most useful as measures of vaccine potency. Careful immune monitoring in association with larger scale clinical trials ultimately may enable the correlation of monitoring results with clinical benefit.

Authors
Keilholz, U; Weber, J; Finke, JH; Gabrilovich, DI; Kast, WM; Disis, ML; Kirkwood, JM; Scheibenbogen, C; Schlom, J; Maino, VC; Lyerly, HK; Lee, PP; Storkus, W; Marincola, F; Worobec, A; Atkins, MB
MLA Citation
Keilholz, U, Weber, J, Finke, JH, Gabrilovich, DI, Kast, WM, Disis, ML, Kirkwood, JM, Scheibenbogen, C, Schlom, J, Maino, VC, Lyerly, HK, Lee, PP, Storkus, W, Marincola, F, Worobec, A, and Atkins, MB. "Immunologic monitoring of cancer vaccine therapy: results of a workshop sponsored by the Society for Biological Therapy." J Immunother 25.2 (March 2002): 97-138. (Review)
PMID
12074049
Source
pubmed
Published In
Journal of Immunotherapy
Volume
25
Issue
2
Publish Date
2002
Start Page
97
End Page
138

Pocket Surgery

Pocket Surgery contains brief synopses of the basic steps of common operative procedures, including general/transplant surgery, vascular surgery, pediatric surgery, and other invasive procedures.

Authors
Mosca, PJ; Clark, LA; Lyerly, HK
MLA Citation
Mosca, PJ, Clark, LA, and Lyerly, HK. Pocket Surgery. Lippincott Williams & Wilkins, January 2002.
Source
google-books
Publish Date
2002

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

Thoracic paravertebral blockade for breast sentinel lymph node biopsy: Experience in 137 patients

Authors
White, DC; Hamza, A; Nielson, K; Lyerly, HK; Steele, SM; Pruitt, SK; Leight, GS; Olson, JA
MLA Citation
White, DC, Hamza, A, Nielson, K, Lyerly, HK, Steele, SM, Pruitt, SK, Leight, GS, and Olson, JA. "Thoracic paravertebral blockade for breast sentinel lymph node biopsy: Experience in 137 patients." January 2002.
Source
wos-lite
Published In
Annals of Surgical Oncology
Volume
9
Issue
1
Publish Date
2002
Start Page
S56
End Page
S57

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

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 (2002): 313-322.
Source
scival
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

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

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

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

Quantitating functional CD8+T cell response to viral antigens

Authors
Hobeika, AC; Peplinski, SL; Clay, TM; Lyerly, HK
MLA Citation
Hobeika, AC, Peplinski, SL, Clay, TM, and Lyerly, HK. "Quantitating functional CD8+T cell response to viral antigens." March 7, 2001.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
15
Issue
4
Publish Date
2001
Start Page
A304
End Page
A304

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

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

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

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

Blocking the initiation of coagulation by RNA aptamers to factor VIIa.

The tissue factor/factor VIIa complex is thought to be the primary initiator of most physiologic blood coagulation events. Because of its proximal role in this process, we sought to generate new inhibitors of tissue factor/factor VIIa activity by targeting factor VIIa. We employed a combinatorial RNA library and in vitro selection methods to isolate a high affinity, nuclease-resistant RNA ligand that binds specifically to coagulation factor VII/VIIa. This RNA inhibits the tissue factor-dependent activation of factor X by factor VIIa. Kinetic analyses of the mechanism of action of this RNA suggest that it antagonizes factor VIIa activity by preventing formation of a functional factor VII/tissue factor complex. Furthermore, this RNA significantly prolongs the prothrombin time of human plasma in a dose dependent manner, and has an in vitro half-life of approximately 15 h in human plasma. Thus, this RNA ligand represents a novel class of anticoagulant agents directed against factor VIIa.

Authors
Rusconi, CP; Yeh, A; Lyerly, HK; Lawson, JH; Sullenger, BA
MLA Citation
Rusconi, CP, Yeh, A, Lyerly, HK, Lawson, JH, and Sullenger, BA. "Blocking the initiation of coagulation by RNA aptamers to factor VIIa." Thromb Haemost 84.5 (November 2000): 841-848.
PMID
11127866
Source
pubmed
Published In
Thrombosis and haemostasis
Volume
84
Issue
5
Publish Date
2000
Start Page
841
End Page
848

Tumor-specific recognition of human myeloma cells by idiotype-induced CD8(+) T cells.

Immunoglobulin secreted by myeloma cells contains a unique antigenic determinant (idiotype [Id]) that may serve as a tumor-specific antigen. Although Id-protein-specific T-cell responses have been reported in patients with myeloma, it is not known whether primary myeloma tumor cells can present naturally processed Id peptides on their surface as a target. We immunized 2 healthy human stem-cell donors with Id proteins from their recipients. T cells from the immunized donors released high levels of T-helper 1-type cytokines in response to stimulation with myeloma cells from their recipients. The T-cell-mediated cytokine response to tumor cells was blocked by a major histocompatibility complex (MHC) class I monoclonal antibody, whereas the response to soluble Id protein was dependent on MHC class II. To investigate whether Id-specific CD8(+) T cells can recognize and kill autologous myeloma cells, we generated T cells from peripheral blood mononuclear cells from a third patient with myeloma by means of in vitro stimulation with autologous dendritic cells pulsed with Id protein. Tumor-specific lysis of myeloma cells was demonstrated by the lack of killing of autologous nonmalignant B cells or natural killer-sensitive K562 cells. Lysis of autologous myeloma targets was restricted by MHC class I molecules. These data represent the first report of class I-restricted T-cell recognition of fresh autologous myeloma targets and formally demonstrate that human myeloma cells can serve as targets of an Id-specific T-cell response. (Blood. 2000;96:2828-2833)

Authors
Li, Y; Bendandi, M; Deng, Y; Dunbar, C; Munshi, N; Jagannath, S; Kwak, LW; Lyerly, HK
MLA Citation
Li, Y, Bendandi, M, Deng, Y, Dunbar, C, Munshi, N, Jagannath, S, Kwak, LW, and Lyerly, HK. "Tumor-specific recognition of human myeloma cells by idiotype-induced CD8(+) T cells." Blood 96.8 (October 15, 2000): 2828-2833.
PMID
11023518
Source
pubmed
Published In
Blood
Volume
96
Issue
8
Publish Date
2000
Start Page
2828
End Page
2833

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

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection.

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Authors
Markert, ML; Hicks, CB; Bartlett, JA; Harmon, JL; Hale, LP; Greenberg, ML; Ferrari, G; Ottinger, J; Boeck, A; Kloster, AL; McLaughlin, TM; Bleich, KB; Ungerleider, RM; Lyerly, HK; Wilkinson, WE; Rousseau, FS; Heath-Chiozzi, ME; Leonard, JM; Haase, AT; Shaw, GM; Bucy, RP; Douek, DC; Koup, RA; Haynes, BF; Bolognesi, DP; Weinhold, KJ
MLA Citation
Markert, ML, Hicks, CB, Bartlett, JA, Harmon, JL, Hale, LP, Greenberg, ML, Ferrari, G, Ottinger, J, Boeck, A, Kloster, AL, McLaughlin, TM, Bleich, KB, Ungerleider, RM, Lyerly, HK, Wilkinson, WE, Rousseau, FS, Heath-Chiozzi, ME, Leonard, JM, Haase, AT, Shaw, GM, Bucy, RP, Douek, DC, Koup, RA, Haynes, BF, Bolognesi, DP, and Weinhold, KJ. "Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection." AIDS Res Hum Retroviruses 16.5 (March 20, 2000): 403-413.
PMID
10772526
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
16
Issue
5
Publish Date
2000
Start Page
403
End Page
413
DOI
10.1089/088922200309061

Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells.

Unique patient-specific tumor antigens may constitute the dominant antigens in the antitumor immune response. Hence, vaccination with the patient's own repertoire of tumor antigens may offer a superior strategy to elicit protective immunity. We have shown previously that dendritic cells transfected with mRNA isolated from tumor cells stimulate potent CTL responses and engender protective immunity in tumor-bearing mice. In the current study, we demonstrate that tumor mRNA, isolated from murine tumor cell lines or from primary human tumor cells microdissected from frozen tissue sections, can be amplified without loss of function. This study provides the foundations for an effective and broadly applicable treatment that does not require the characterization of the relevant antigenic profile in each patient and will not be limited by tumor tissue availability for antigen preparation.

Authors
Boczkowski, D; Nair, SK; Nam, JH; Lyerly, HK; Gilboa, E
MLA Citation
Boczkowski, D, Nair, SK, Nam, JH, Lyerly, HK, and Gilboa, E. "Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells." Cancer Res 60.4 (February 15, 2000): 1028-1034.
PMID
10706120
Source
pubmed
Published In
Cancer Research
Volume
60
Issue
4
Publish Date
2000
Start Page
1028
End Page
1034

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

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

FLT3-ligand (FLT3L) mobilization of dendritic cells (DC) in patients with metastatic colon cancer.

Authors
Morse, M; Nair, S; Fernandez-Castal, M; Caron, D; Proia, A; Lyerly, HK
MLA Citation
Morse, M, Nair, S, Fernandez-Castal, M, Caron, D, Proia, A, and Lyerly, HK. "FLT3-ligand (FLT3L) mobilization of dendritic cells (DC) in patients with metastatic colon cancer." November 15, 1999.
Source
wos-lite
Published In
Blood
Volume
94
Issue
10
Publish Date
1999
Start Page
48A
End Page
48A

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

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

RNA aptamers as potential anticoagulants directed against factor VIIa function

Authors
Rusconi, CP; Yeh, A; Lyerly, HK; Lawson, JH; Sullenger, BA
MLA Citation
Rusconi, CP, Yeh, A, Lyerly, HK, Lawson, JH, and Sullenger, BA. "RNA aptamers as potential anticoagulants directed against factor VIIa function." August 1999.
Source
wos-lite
Published In
Thrombosis and haemostasis
Publish Date
1999
Start Page
468
End Page
468

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

Isolation of RNA aptamers to block coagulation

Authors
Sullenger, B; Rusconi, C; Yeh, A; Lawson, J; Lyerly, H
MLA Citation
Sullenger, B, Rusconi, C, Yeh, A, Lawson, J, and Lyerly, H. "Isolation of RNA aptamers to block coagulation." FASEB JOURNAL 13.7 (April 23, 1999): A1320-A1320.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
13
Issue
7
Publish Date
1999
Start Page
A1320
End Page
A1320

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

Sabiston Textbook of Surgery The Biological Basis of Modern Surgical Practice

Authors
Sabiston, DC; Lyerly, HK
MLA Citation
Sabiston, DC, and Lyerly, HK. Sabiston Textbook of Surgery The Biological Basis of Modern Surgical Practice. 1999.
Source
google-books
Publish Date
1999

In vivo administration of a suicide gene inhibits tumour progression in breast cancer

Authors
Clary, B; Wheatley, G; Lyerly, HK
MLA Citation
Clary, B, Wheatley, G, and Lyerly, HK. "In vivo administration of a suicide gene inhibits tumour progression in breast cancer." November 1998.
Source
wos-lite
Published In
British Journal of Surgery
Volume
85
Issue
11
Publish Date
1998
Start Page
1570
End Page
1570

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

AIDS-related malignancies.

In the US over one million persons are currently infected with the HIV, over half a million have had AIDS, and over 300,000 have died from AIDS. Worldwide, it is estimated that more than 17 million people are currently infected with HIV, and over 1,200,000 cases of AIDS have been reported to the World Health Organization. By some estimates, up to 40% of patients with AIDS will ultimately develop some form of cancer. Non-Hodgkin's lymphoma, Kaposi's sarcoma and invasive cervical cancer have a higher incidence in persons with HIV infection and all three are AIDS-defining illnesses. In addition, several reports suggest that a number of other malignancies may occur at an increased incidence in persons with HIV infection, including squamous-cell carcinoma of the head, neck and anus, plasmacytoma, melanoma, small-cell lung cancer, basal-cell cancer, and germ-cell tumours. Clinicians should become familiar with HIV-related malignancies as their incidence is expected to further increase as more effective therapies for HIV and associated opportunistic infections allow patients to live longer in an advanced state of immunodeficiency. In the current article, we will review the clinical and therapeutic aspects of the most common AIDS-related malignancies including non-Hodgkin's and Hodgkin's lymphomas, Kaposi's sarcoma and anogenital epithelial neoplasias.

Authors
Smith, C; Lilly, S; Mann, KP; Livingston, E; Myers, S; Lyerly, HK; Miralles, GD
MLA Citation
Smith, C, Lilly, S, Mann, KP, Livingston, E, Myers, S, Lyerly, HK, and Miralles, GD. "AIDS-related malignancies." Ann Med 30.4 (August 1998): 323-344. (Review)
PMID
9783831
Source
pubmed
Published In
Annals of Medicine (Informa)
Volume
30
Issue
4
Publish Date
1998
Start Page
323
End Page
344

Dendritic cells improve the generation of Epstein-Barr virus-specific cytotoxic T lymphocytes for the treatment of posttransplantation lymphoma.

BACKGROUND: The use of immunosuppressive therapies after solid organ transplantation has been shown to increase a patient's risk for Epstein-Barr virus (EBV)-associated lymphoma. A potential therapy for this disorder is the adoptive transfer of EBV-specific cytotoxic T lymphocytes (CTLs). We proposed that dendritic cells (DCs) could be loaded with EBV antigens and be used to improve the in vitro generation of EBV-specific CTLs. METHODS: Autologous EBV-transformed B-lymphoblastoid cell lines (BLCLs) were generated from normal donors, and CTLs were initiated by culturing peripheral blood mononuclear cells with DCs alone, disrupted BLCLs alone, intact, irradiated BLCLs alone, and DCs loaded with disrupted BLCLs. Lytic activities were determined with a 4-hour chromium-release assay against autologous BLCLs, and statistical calculations were performed by a Student t test assuming equal variance. RESULTS: The lytic activity of CTLs generated with DCs loaded with disrupted BLCLs reached 78% and was statistically significant (P < .01) at all effector/target ratios compared with CTLs generated with DCs alone, disrupted BLCLs alone, or intact BLCLs alone. Total numbers of CTLs were also greater than those of control groups for DCs loaded with disrupted BLCLs. CONCLUSIONS: DCs improved the in vitro generation of EBV-specific CTLs as evidenced by this group's significantly increased lytic activity over that of the control group. The improved lytic activity of DC-generated EBV-CTLs suggests that adoptive transfer of these cells could lead to a more effective immunotherapeutic response against posttransplantation EBV-associated lymphoma.

Authors
Wheatley, GH; McKinnon, KP; Iacobucci, M; Mahon, S; Gelber, C; Lyerly, HK
MLA Citation
Wheatley, GH, McKinnon, KP, Iacobucci, M, Mahon, S, Gelber, C, and Lyerly, HK. "Dendritic cells improve the generation of Epstein-Barr virus-specific cytotoxic T lymphocytes for the treatment of posttransplantation lymphoma." Surgery 124.2 (August 1998): 171-176.
PMID
9706135
Source
pubmed
Published In
Surgery
Volume
124
Issue
2
Publish Date
1998
Start Page
171
End Page
176

End points in the analysis of breast cancer survival: Relapse versus death from tumor - Discussion

Authors
Beauchamp, RD; Edwards, ; Lyerly, HK; Cance, WG
MLA Citation
Beauchamp, RD, Edwards, , Lyerly, HK, and Cance, WG. "End points in the analysis of breast cancer survival: Relapse versus death from tumor - Discussion." SURGERY 124.2 (August 1998): 202-202.
Source
wos-lite
Published In
Surgery
Volume
124
Issue
2
Publish Date
1998
Start Page
202
End Page
202

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

Transcriptional targeting for cancer gene therapy.

Novel treatment strategies incorporating gene transfer technology represent a new frontier in the treatment of cancer made possible through recent developments in molecular biology. Targeting of gene therapy strategies that rely on in situ gene modifications can theoretically occur at the gene entry or gene expression level. Regulation of gene transcription is made possible through the incorporation of cell-specific promoter and enhancer sequences within the transgene construct. This article provides a brief review of transcriptional processes and a description of the most widely studied cell-specific regulatory elements.

Authors
Clary, BM; Lyerly, HK
MLA Citation
Clary, BM, and Lyerly, HK. "Transcriptional targeting for cancer gene therapy." Surg Oncol Clin N Am 7.3 (July 1998): 565-574. (Review)
PMID
9624217
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
7
Issue
3
Publish Date
1998
Start Page
565
End Page
574

Immunotherapy of cancer with dendritic-cell-based vaccines.

Animal studies have shown that vaccination with genetically modified tumor cells or with dendritic cells (DC) pulsed with tumor antigens are potent strategies to elicit protective immunity in tumor-bearing animals, more potent than "conventional" strategies that have been tested in clinical settings with limited success. While both vaccination strategies are forms of cell therapy requiring complex and costly ex vivo manipulations of the patient's cells, current protocols using dendritic cells are considerably simpler and would be more widely available. Vaccination with defined tumor antigens presented by DC has obvious appeal. However, in view of the expected emergence of antigen-loss variants as well as natural immunovariation, effective vaccine formulations must contain mixtures of commonly, if not universally, expressed tumor antigens. When, or even if, such common tumor antigens will be identified cannot be, predicted, however. Thus, for the foreseeable future, vaccination with total-tumor-derived material as source of tumor antigens may be preferable to using defined tumor antigens. Vaccination with undefined tumor-derived antigens will be limited, however, by the availability of sufficient tumor tissue for antigen preparation. Because the mRNA content of single cells can be amplified, tumor mRNA, or corresponding cDNA libraries, offer an unlimited source of tumor antigens. DC transfected with tumor RNA were shown to engender potent antitumor immunity in animal studies. Thus, immunotherapy using autologous DC loaded with unfractionated tumor-derived antigens in the form of RNA emerges as a potentially powerful and broadly useful vaccination strategy for cancer patients.

Authors
Gilboa, E; Nair, SK; Lyerly, HK
MLA Citation
Gilboa, E, Nair, SK, and Lyerly, HK. "Immunotherapy of cancer with dendritic-cell-based vaccines." Cancer Immunol Immunother 46.2 (April 1998): 82-87. (Review)
PMID
9558003
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
46
Issue
2
Publish Date
1998
Start Page
82
End Page
87

Use of paravertebral block anesthesia in the surgical management of breast cancer: experience in 156 cases.

OBJECTIVE: To assess safety and efficacy of the regional anesthetic technique paravertebral block for operative treatment of breast cancer, and to compare postoperative pain, nausea, vomiting, and length of hospital stay in patients undergoing breast surgery using paravertebral block and general anesthesia. BACKGROUND: General anesthesia is currently the standard technique used for surgical treatment of breast cancer. Increasing hospital costs have focused attention on reducing the length of hospital stay for these patients. However, the side effects and complications of general anesthesia preclude ambulatory surgery for most patients undergoing breast surgery. In April 1994, the authors initiated the use of paravertebral block anesthesia for patients undergoing primary breast cancer surgery. A review of our early experience revealed that this regional anesthetic technique enables effective anesthesia for operative procedures of the breast and axilla, reduces postoperative nausea and vomiting, and provides prolonged postoperative sensory block that minimizes narcotic requirements. METHODS: A retrospective analysis of 145 consecutive patients undergoing 156 breast cancer operations using paravertebral block and 100 patients undergoing general anesthesia during a 2-year period was performed. Anesthetic effectiveness and complications, inpatient experience with postoperative pain, nausea, vomiting, and length of stay were measured. RESULTS: Surgery was successfully completed in 85% of the cases attempted by using paravertebral block alone, and in 91% of the cases, surgery was completed by using paravertebral block supplemented with local anesthetic. There was a 2.6% incidence of complications associated with block placement. Twenty percent of patients in the paravertebral group required medication for nausea and vomiting during their hospital stay compared with 39% in the general anesthesia group. Narcotic analgesia was required in 98% of general anesthesia patients, as opposed to 25% of patients undergoing paravertebral block. Ninety-six percent of patients having paravertebral block anesthesia were discharged within the day of surgery, compared with 76% of patients who had a general anesthetic. CONCLUSIONS: Paravertebral block can be used to perform major operations for breast cancer with minimal complications and a low rate of conversion to general anesthesia. Paravertebral block markedly improves the quality of recovery after breast cancer surgery and provides the patient with the option of ambulatory discharge.

Authors
Coveney, E; Weltz, CR; Greengrass, R; Iglehart, JD; Leight, GS; Steele, SM; Lyerly, HK
MLA Citation
Coveney, E, Weltz, CR, Greengrass, R, Iglehart, JD, Leight, GS, Steele, SM, and Lyerly, HK. "Use of paravertebral block anesthesia in the surgical management of breast cancer: experience in 156 cases." Ann Surg 227.4 (April 1998): 496-501.
PMID
9563536
Source
pubmed
Published In
Annals of Surgery
Volume
227
Issue
4
Publish Date
1998
Start Page
496
End Page
501

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

Gene therapy and pancreatic cancer.

In the short time since the inception of gene therapy, significant advances have been realized. Although this progress has not realized definitive breakthroughs in the treatment of solid organ tumors, including pancreatic cancer, the hope is that advances will come with improved gene delivery systems and alternative approaches. The authors review the history of gene therapy, the current treatment strategies and delivery systems, the preclinical studies on its application to pancreatic cancer, and provide an up-to-date list of federally approved gene therapy cancer trials.

Authors
Clary, BM; Lyerly, HK
MLA Citation
Clary, BM, and Lyerly, HK. "Gene therapy and pancreatic cancer." Surg Oncol Clin N Am 7.1 (January 1998): 217-249. (Review)
PMID
9443997
Source
pubmed
Published In
Surgical Oncology Clinics of North America
Volume
7
Issue
1
Publish Date
1998
Start Page
217
End Page
249

Activation/maturation of Peripheral blood derived dendritic cells by CD40 ligand

Authors
Deng, YP; St Peter, M; Baseden, K; Thomas, E; Lyerly, K
MLA Citation
Deng, YP, St Peter, M, Baseden, K, Thomas, E, and Lyerly, K. "Activation/maturation of Peripheral blood derived dendritic cells by CD40 ligand." JOURNAL OF LEUKOCYTE BIOLOGY (1998): 31-31.
Source
wos-lite
Published In
Journal of leukocyte biology
Publish Date
1998
Start Page
31
End Page
31

Sylvester o'halloran surgical scientific meeting - Proceedings of meeting held 7th & 8th March 1997 in Charles parsons theatre, university of Limerick

Authors
Fulton, GJ; Davies, MG; O'Hagen, P; Rasheed, A; Kelly, C; Kay, E; Fitzgerald, S; Bouchier-Hayes, D; Leahy, A; Fennessy, F; Kelly, C; Fitzgerald, P; Bouchier-Hayes, D; Khosraviani, K; Weir, HP; Williamson, K; Wilson, R; Moorehead, RJ; Rowlands, BJ; Morrissey, D; O'Connell, J; Lynch, D; O'Sullivan, C; Shanahan, F; Collins, JK; Kelly, JL; Soberg, CC; Lyons, A; Mannick, JA; Lederer, JA; Chen, C; Kelly, C; Leahy, A; Bouchier-Hayes, DJ; Fitzsimons, H; O'Hanlon, DM; Curran, C; Canney, M; Morris, S et al.
MLA Citation
Fulton, GJ, Davies, MG, O'Hagen, P, Rasheed, A, Kelly, C, Kay, E, Fitzgerald, S, Bouchier-Hayes, D, Leahy, A, Fennessy, F, Kelly, C, Fitzgerald, P, Bouchier-Hayes, D, Khosraviani, K, Weir, HP, Williamson, K, Wilson, R, Moorehead, RJ, Rowlands, BJ, Morrissey, D, O'Connell, J, Lynch, D, O'Sullivan, C, Shanahan, F, Collins, JK, Kelly, JL, Soberg, CC, Lyons, A, Mannick, JA, Lederer, JA, Chen, C, Kelly, C, Leahy, A, Bouchier-Hayes, DJ, Fitzsimons, H, O'Hanlon, DM, Curran, C, Canney, M, and Morris, S et al. "Sylvester o'halloran surgical scientific meeting - Proceedings of meeting held 7th & 8th March 1997 in Charles parsons theatre, university of Limerick." 1998.
Source
scival
Published In
Irish Journal of Medical Science
Volume
167
Issue
4 Supplement
Publish Date
1998
Start Page
1
End Page
16
DOI
10.1007/BF02937899

Cancer immunotherapy with tumor RNA transfected dendritic cell vaccines.

Authors
Nair, SK; Morse, M; Boczkowski, D; Lyerly, HK; Gilboa, E
MLA Citation
Nair, SK, Morse, M, Boczkowski, D, Lyerly, HK, and Gilboa, E. "Cancer immunotherapy with tumor RNA transfected dendritic cell vaccines." 1998.
Source
wos-lite
Published In
Journal of leukocyte biology
Publish Date
1998
Start Page
88
End Page
88

Immunotherapy of cancer with dendritic cell-based tumor vaccines

Authors
Gilboa, E; Nair, SK; Morse, M; Boczkowski, D; Deng, Y; Lyerly, HK
MLA Citation
Gilboa, E, Nair, SK, Morse, M, Boczkowski, D, Deng, Y, and Lyerly, HK. "Immunotherapy of cancer with dendritic cell-based tumor vaccines." 1998.
Source
wos-lite
Published In
Annals of Oncology
Volume
9
Publish Date
1998
Start Page
7
End Page
7

Generation of autologous CD4+ T lymphocyte clones specific for precursor-B (pre-B) lymphoblasts via dendritic cell (DC) presentation

Authors
Laughlin, MJ; McKinnon, K; Demarest, J; Koropchak, CM; Weinhold, K; Lyerly, HK; Gilboa, E; Kaufman, R; DeSombre, K; Iacobucci, M; Adams, D; Cook, JM; Martinek, L; DeOliveira, D; Kurtzberg, J
MLA Citation
Laughlin, MJ, McKinnon, K, Demarest, J, Koropchak, CM, Weinhold, K, Lyerly, HK, Gilboa, E, Kaufman, R, DeSombre, K, Iacobucci, M, Adams, D, Cook, JM, Martinek, L, DeOliveira, D, and Kurtzberg, J. "Generation of autologous CD4+ T lymphocyte clones specific for precursor-B (pre-B) lymphoblasts via dendritic cell (DC) presentation." November 15, 1997.
Source
wos-lite
Published In
Blood
Volume
90
Issue
10
Publish Date
1997
Start Page
826
End Page
826

Active immunization using dendritic cells mixed with tumor cells inhibits the growth of primary breast cancer.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells regarded as crucial in the priming of an immune response. The goal of our study was to test whether bone marrow-generated DCs are capable of inducing protective immunity against a murine breast carcinoma (4T1). METHODS: DCs were grown from Balb/c mice by culturing lymphocyte-immunodepleted bone marrow in murine granulocyte-macrophage colony-stimulating factor containing medium for 10 days. Balb/c mice (five to eight per group) were immunized intradermally with 1 x 10(6) DCs mixed with 2 x 10(6) lethally irradiated 4T1 cells on day 0. Mice in control groups were given intradermal inoculations of phosphate-buffered saline solution, 1 x 10(6) DCs, or lethally irradiated 4T1 cells alone. Booster intraperitoneal immunizations of 2 x 10(6) lethally irradiated 4T1 cells were given on days 7 and 14. All mice were challenged with 5 x 10(3) 4T1 cells subcutaneously 7 days after the final immunization. Animals were examined daily, and tumor volume was recorded twice weekly with calipers. RESULTS: At 21 days there was a significant reduction in tumor growth in mice immunized with DCs mixed with irradiated 4T1 cells as compared with the control groups (p = 0.0005, Kruskal-Wallis test). CONCLUSIONS: These results suggest that DCs mixed with tumor cells as a source of undefined tumor antigen can induce an effective antitumor immune response. This finding provides a rationale for the use of cultured DCs in immunotherapy of breast and other cancers.

Authors
Coveney, E; Wheatley, GH; Lyerly, HK
MLA Citation
Coveney, E, Wheatley, GH, and Lyerly, HK. "Active immunization using dendritic cells mixed with tumor cells inhibits the growth of primary breast cancer." Surgery 122.2 (August 1997): 228-234.
PMID
9288127
Source
pubmed
Published In
Surgery
Volume
122
Issue
2
Publish Date
1997
Start Page
228
End Page
234

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

Local recurrence of rectal cancer: evaluation with F-18 fluorodeoxyglucose PET imaging.

BACKGROUND: Positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) is a useful technique for detection of malignancy. The purpose of this study was to determine if FDG-PET scanning using visual and quantitative analyses can identify patients with recurrent colorectal tumor following abdominoperineal resection. METHODS: Eighteen patients were evaluated for possible local recurrence of rectal carcinoma following abdominoperineal resection. The clinical presentation included rising carcinoembryonic antigen levels (n = 5), increasing size of a presacral mass on computed tomography or magnetic resonance (n = 13), or local symptoms (n = 3). Axial PET images of the pelvis were obtained following an injection of 10 mCi of FDG prior to biopsy. Quantitative analysis was performed by calculation of a standardized uptake ratio (SUR), and the images were interpreted by two radiologists in consensus. FDG-PET findings were correlated with histological or cytological findings and with the clinical outcome. RESULTS: Recurrent malignancy was confirmed in 13 patients by surgery (n = 8) or percutaneous biopsy (n = 5). Benign lesions were confirmed in five patients by surgery (n = 1), biopsy (n = 3), or clinical follow up (n = 1). Visual analysis of the FDG-PET data had a sensitivity of 92.3% (12/13) for recurrent disease (95% confidence limits; 63.9%, 99.8%) and a specificity of 80% (4/5; 95% confidence limits; 28.3%, 99.4%). SUR values were significantly higher in malignant lesions (range = 2.92-19.74, mean = 6.89) than in benign ones (range = 1.40-3.47, mean = 1.96; p = 0.002). CONCLUSION: FDG-PET is an accurate technique for detection of locally recurrent colorectal carcinoma. Visual analysis is equivalent to quantitative analysis for detection of disease.

Authors
Keogan, MT; Lowe, VJ; Baker, ME; McDermott, VG; Lyerly, HK; Coleman, RE
MLA Citation
Keogan, MT, Lowe, VJ, Baker, ME, McDermott, VG, Lyerly, HK, and Coleman, RE. "Local recurrence of rectal cancer: evaluation with F-18 fluorodeoxyglucose PET imaging." Abdom Imaging 22.3 (May 1997): 332-337.
PMID
9107663
Source
pubmed
Published In
Abdominal Imaging
Volume
22
Issue
3
Publish Date
1997
Start Page
332
End Page
337

Adoptive immunotherapy using autologous EBV specific cytotoxic T lymphocytes in an HIV infected patient with refractory Epstein Barr virus expressing B cell lymphoma

Authors
Wheatley, GH; McKinnon, K; Lilly, S; Smith, C; Lyerly, HK
MLA Citation
Wheatley, GH, McKinnon, K, Lilly, S, Smith, C, and Lyerly, HK. "Adoptive immunotherapy using autologous EBV specific cytotoxic T lymphocytes in an HIV infected patient with refractory Epstein Barr virus expressing B cell lymphoma." April 1, 1997.
Source
wos-lite
Published In
Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association
Volume
14
Issue
4
Publish Date
1997
Start Page
147
End Page
147

Untitled

Authors
Weltz, CR; Greengrass, RA; Lyerly, K
MLA Citation
Weltz, CR, Greengrass, RA, and Lyerly, K. "Untitled." ANNALS OF SURGERY 225.3 (March 1997): 341-341.
Source
wos-lite
Published In
Annals of Surgery
Volume
225
Issue
3
Publish Date
1997
Start Page
341
End Page
341
DOI
10.1097/00000658-199703000-00019

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

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

Textbook of Surgery Pocket Companion

The Pocket Companion is designed to provide an immediate source of key information on each surgical topic covered in the Textbook of Surgery: The Biological Basis of Modern Surgical Practice. It should be especially helpful in urgent ...

Authors
Sabiston, DC; Lyerly, HK
MLA Citation
Sabiston, DC, and Lyerly, HK. Textbook of Surgery Pocket Companion. W B Saunders Company, 1997.
Source
google-books
Publish Date
1997

Generation of T lymphocyte clones specific for acute lymphoblastic leukemia (ALL) via dendritic cell (DC) presentation.

Authors
Laughlin, MJ; Kurtzberg, J; Weinhold, K; Ferrari, G; Pilgrim, A; Gelber, C; Nair, S; Gilboa, E; Smith, CA; Martinek, L; DeOliveira, D; Lyerly, HK
MLA Citation
Laughlin, MJ, Kurtzberg, J, Weinhold, K, Ferrari, G, Pilgrim, A, Gelber, C, Nair, S, Gilboa, E, Smith, CA, Martinek, L, DeOliveira, D, and Lyerly, HK. "Generation of T lymphocyte clones specific for acute lymphoblastic leukemia (ALL) via dendritic cell (DC) presentation." November 15, 1996.
Source
wos-lite
Published In
Blood
Volume
88
Issue
10
Publish Date
1996
Start Page
1487
End Page
1487

Active immunotherapy of pancreatic cancer with tumor cells genetically engineered to secrete multiple cytokines.

BACKGROUND: Vaccination of tumor-bearing animals with tumor cells genetically engineered to secrete cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) has been shown to induce effective tumor-specific immune responses capable of inhibiting local and metastatic disease. Previous unsuccessful attempts to enhance this immune response by means of the secretion of multiple cytokines possessing different immunologic mechanisms of action may have been due to the inherent inefficiency of the gene transfer systems used. We postulated that tumor cells genetically engineered by means of a novel gene transfer method resulting in high level secretion of both cytokines would be more effective than tumor cells secreting a single cytokine in inhibiting the growth of existing tumors. METHODS: Nonimmunogenic, murine pancreatic cancer cells (Panc02) were engineered to secrete IL-2, IFN-gamma, IL-2 and IFN-gamma, or neomycin phosphotransferase. Mice were inoculated with 5 x 10(5) parental Panc02 tumor cells subcutaneously. Beginning 3 days later, animals then received a series of four weekly vaccinations with irradiated Panc02/Neo, Panc02/IL2, Panc02/IFN, or Panc02/IL-2/IFN. RESULTS: Treatment with Panc02/Neo, Panc02/IL-2, or Panc02/IFN resulted in 0%, 40%, and 30% tumor-free survival, respectively. In contrast, 80% of animals vaccinated with Panc02/IL2/IFN were free of tumor at 100 days. All animals free of disease were resistant to subsequent tumor challenges. CONCLUSIONS: These data show that vaccination with tumor cells that secrete high levels of multiple cytokines was more effective in treating established pancreatic tumors and represents an improvement over existing single cytokine strategies.

Authors
Clary, BM; Coveney, EC; Blazer, DG; Philip, R; Lyerly, HK
MLA Citation
Clary, BM, Coveney, EC, Blazer, DG, Philip, R, and Lyerly, HK. "Active immunotherapy of pancreatic cancer with tumor cells genetically engineered to secrete multiple cytokines." Surgery 120.2 (August 1996): 174-181.
PMID
8751580
Source
pubmed
Published In
Surgery
Volume
120
Issue
2
Publish Date
1996
Start Page
174
End Page
181

Generation of clinically relevant IL-2 cytokine transgene expression in 3 gastrointestinal cancer cell lines using cationic polymer-mediated gene transfer.

Authors
Wheatley, GH; Mundorf, JB; Philip, R; Lyerly, HK
MLA Citation
Wheatley, GH, Mundorf, JB, Philip, R, and Lyerly, HK. "Generation of clinically relevant IL-2 cytokine transgene expression in 3 gastrointestinal cancer cell lines using cationic polymer-mediated gene transfer." April 1996.
Source
wos-lite
Published In
Gastroenterology
Volume
110
Issue
4
Publish Date
1996
Start Page
A613
End Page
A613

Gene therapy in surgery.

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Gene therapy in surgery." Ann Surg 223.2 (February 1996): 115-.
PMID
8597503
Source
pubmed
Published In
Annals of Surgery
Volume
223
Issue
2
Publish Date
1996
Start Page
115

MAGE-1-specific precursor cytotoxic T-lymphocytes present among tumor-infiltrating lymphocytes from a patient with breast cancer: characterization and antigen-specific activation.

A potential target for development of tumor-specific immunotherapeutic strategies is the MAGE-1 gene. We have utilized a recently developed recombinant canarypox (ALVAC) virus vector containing the MAGE-1 gene (vCP235) to activate CTLs from a breast cancer patient bearing a MAGE-1+ tumor. Tumor-infiltrating lymphocytes (TILs) obtained from the tumor of a patient were stimulated in vitro with irradiated autologous peripheral blood mononuclear cells acutely infected with the vCP235 construct. These TILs preferentially expanded approximately 6-fold over a 16-day culture period and specifically recognized an allogeneic transformed B-cell line acutely infected with a vaccinia-MAGE-1 recombinant targeting vector (vP1188) in the context of HLA-A2 and/or B7. TCR V beta analysis of in vitro expanded T cells by a quantitative multiprobe RNase protection assay revealed preferential expansion of TCR V beta 6.3 and V beta 6.4. In addition, homologous T-cell receptor beta CDR3 joining sequences were found in the in vitro stimulated cultures. These results suggest that tumor antigen-specific, MHC-restricted CTLs may be derived from precursor CTLs present in TILs obtained from patients with MAGE-1+ tumors by in vitro stimulation with recombinant avipox MAGE-1 virus-infected autologous cells. Collectively, these findings provide a rationale for tumor-associated antigen-based immunization as a means of activating precursor CTLs residing in patients with tumors expressing defined tumor-associated antigens such as MAGE-1.

Authors
Toso, JF; Oei, C; Oshidari, F; Tartaglia, J; Paoletti, E; Lyerly, HK; Talib, S; Weinhold, KJ
MLA Citation
Toso, JF, Oei, C, Oshidari, F, Tartaglia, J, Paoletti, E, Lyerly, HK, Talib, S, and Weinhold, KJ. "MAGE-1-specific precursor cytotoxic T-lymphocytes present among tumor-infiltrating lymphocytes from a patient with breast cancer: characterization and antigen-specific activation." Cancer Res 56.1 (January 1, 1996): 16-20.
PMID
8548758
Source
pubmed
Published In
Cancer Research
Volume
56
Issue
1
Publish Date
1996
Start Page
16
End Page
20

Gene modification of primary tumor cells for active immunotherapy of human breast and ovarian cancer.

We have previously shown that cationic liposomes facilitate adeno-associated virus (AAV) plasmid transfections of primary and cultured cell types. To test the clinical feasibility of using genetically modified tumor vaccines for the treatment of breast and ovarian cancers, we have constructed an expression plasmid pMP6IL2 and investigated the use of liposome-mediated gene delivery into primary, uncultured human breast and ovarian tumor cells to produce interleukin 2 (IL-2)-secreting tumor cells. We have demonstrated significant levels of IL-2 expression in tumor cell lines and primary breast and ovarian tumor cells using this AAV-based expression plasmid complexed to cationic liposomes. Transfections with the non-AAV plasmid containing the identical expression cassette as the AAV plasmid induced IL-2 expression in the tumor cell line but failed to produce IL-2 in primary tumor cells. Significant levels of IL-2 were induced with the AAV plasmid regardless of liposome compositions used for transfection. The transfected breast cell line and primary tumor cells were able to express the transgene product for up to 28 days after lethal radiation. The transfection efficiency was comparable for both the tumor cell line and primary tumor cells and ranged from 20 to 50% for both cell types as assessed by intracellular IL-2 staining. Although the primary tumor cell preparations consist of mixed population of cells, at least 40% of the tumor cells expressed the transgene as assessed by immunostaining for IL-2. The ability to efficiently express transgenes in freshly isolated, nondividing tumor cells may potentiate active immunotherapy strategies for gene-based cancer treatment.

Authors
Philip, R; Clary, B; Brunette, E; Kilinski, L; Murugesh, D; Sorich, M; Yau, J; Lebkowski, J; Lyerly, HK; Philip, M
MLA Citation
Philip, R, Clary, B, Brunette, E, Kilinski, L, Murugesh, D, Sorich, M, Yau, J, Lebkowski, J, Lyerly, HK, and Philip, M. "Gene modification of primary tumor cells for active immunotherapy of human breast and ovarian cancer." Clin Cancer Res 2.1 (January 1996): 59-68.
PMID
9816091
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
2
Issue
1
Publish Date
1996
Start Page
59
End Page
68

Paravertebral block for breast cancer surgery

Purpose: Major breast cancer surgery is associated with a high incidence of postoperative nausea, vomiting and pain. Regional anaesthesia, with intraoperative sedation, would seem an ideal alternative to general anaesthesia for this type of surgery. We report our initial experience using paravertebral blocks (PVB)to provide anaesthesia for major breast surgery. Methods: Twenty-five patients agreeing to have surgery per formed under paravertebral blocks were studied. Procedures performed varied from simple lumpectomy with axillary dissection to modified radical mastectomy wit axillary dissection. During monitored sedation, blocks opposite spinous processes of C7-T6 were performed using bupivacaine 0.5% with epinephrine, 3-4 ml per segment. Patients were evaluated for 72 hr and were requested to document:(i) when sensation returned (ii) incidence and frequency of nausea or vomiting (iii) degree of discomfort and medication taken. Results: Twenty patients had blocks that required no supplementation. Five patients had blocks that were incomplete. No complications were attributed to the blocks. Post-operatively, patients with successful blocks had minimal nausea, vomiting and pain. No patients found the procedure unsatisfactory. Patients with successful blocks were all very satisfied Conclusion Our initial results show that PVB for breast cancer surgery can be successfully performed in a majority of patients with few side effects. All patients with successful blocks were returned to the ambulatory care unit, bypassing the recovery room. That breast cancer surgery under regional anaesthesia can be safely performed as an ambulatory procedure has the potential for accomplishing major cost-saving.

Authors
Greengrass, R; O'Brien, F; Lyerly, K; Hardman, D; Gleason, D; D'Ercole, F; Steele, S
MLA Citation
Greengrass, R, O'Brien, F, Lyerly, K, Hardman, D, Gleason, D, D'Ercole, F, and Steele, S. "Paravertebral block for breast cancer surgery." Canadian Journal of Anaesthesia 43.8 (1996): 858-861.
PMID
8840066
Source
scival
Published In
Canadian Journal of Anesthesia / Journal canadien d'anesthésie
Volume
43
Issue
8
Publish Date
1996
Start Page
858
End Page
861

Active immunotherapy with transiently transfected cytokine-secreting tumor cells inhibits breast cancer metastases in tumor-bearing animals

Background. Metastatic disease remains the most frequent cause of treatment failure in the management of patients with breast cancer. A novel method that allows delivery of a gene into primary tumor cells was used to generate tumor cell vaccines to inhibit metastasis formation in tumor-bearing hosts. Methods. Inoculation of 2.5 x 104 4T1 murine breast cancer cells into the footpads of BALB/c mice reliably leads to tumor gnowth and pulmonary metastases. Interleukin-2 (IL-2)-secreting 4T1 cells (4T1-pMP6A/IL-2) and control transduced 4T1 cells (4T1-pMP6A) were generated by lipofection with a cationic liposome complexed to an adeno-associated viral plasmid bearing the IL-2 gene (pMP6A/IL-2). Unmodified 4T1 cells were inoculated into the footpads on day 0, and weekly immunization with phosphate-buffered saline solution or 2 x 106 irradiated 4T1, 4T1-pMP6A, or 4T1-pMP6A/IL-2 cells commenced on day 21. Hindlimb amputation was performed when tumors measured 6 mm in diameter. Mice were killed 24 days after amputation, and metastatic disease was determined by weighing lungs at time of harvest. Results. A significant reduction was seen in the pulmonary metastatic load of mice receiving IL-2 gene-modified tumor cell immunization (4T1-pMP6A/IL-2) when compared with mice given control immunizations. Conclusions. These results suggest that active immunization strategies with cytokine gene-modified tumor cells generated by clinically relevant gene delivery systems may prove useful in inhibiting the development of metastases from primary breast cancer.

Authors
Coveney, E; Clary, B; Iacobucci, M; Philip, R; Lyerly, HK
MLA Citation
Coveney, E, Clary, B, Iacobucci, M, Philip, R, and Lyerly, HK. "Active immunotherapy with transiently transfected cytokine-secreting tumor cells inhibits breast cancer metastases in tumor-bearing animals." Surgery 120.2 (1996): 265-273.
PMID
8751592
Source
scival
Published In
Surgery
Volume
120
Issue
2
Publish Date
1996
Start Page
265
End Page
273

Liposome-mediated gene-transfection of human precursor-B lymphoblasts.

Authors
Laughlin, M; Kurtzberg, J; Smith, CA; Lyerly, HK; Weinhold, K; Martinek, L; Boczkowski, D; Gilboa, E
MLA Citation
Laughlin, M, Kurtzberg, J, Smith, CA, Lyerly, HK, Weinhold, K, Martinek, L, Boczkowski, D, and Gilboa, E. "Liposome-mediated gene-transfection of human precursor-B lymphoblasts." November 15, 1995.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
3991
End Page
3991

Gene-transfected leukemia vaccines in acute lymphoblastic leukemia (ALL).

Authors
Laughlin, M; Kurtzberg, J; Smith, CA; Lyerly, HK; Weinhold, K; Martinek, L; Boczkowski, D; Gilboa, E
MLA Citation
Laughlin, M, Kurtzberg, J, Smith, CA, Lyerly, HK, Weinhold, K, Martinek, L, Boczkowski, D, and Gilboa, E. "Gene-transfected leukemia vaccines in acute lymphoblastic leukemia (ALL)." November 15, 1995.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
16415
End Page
16415

Ex vivo generation of antigen specific T cell populations for the treatment of infectious diseases and cancer.

Authors
Lebkowski, JS; Alters, S; Weinhold, K; Paoletti, E; Cox, W; Tartaglia, J; Moody, DJ; Gadol, N; Vertin, B; Gadea, J; Lyerly, HK; Kilinski, L; Okarma, TB; Philip, R
MLA Citation
Lebkowski, JS, Alters, S, Weinhold, K, Paoletti, E, Cox, W, Tartaglia, J, Moody, DJ, Gadol, N, Vertin, B, Gadea, J, Lyerly, HK, Kilinski, L, Okarma, TB, and Philip, R. "Ex vivo generation of antigen specific T cell populations for the treatment of infectious diseases and cancer." November 15, 1995.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
1694
End Page
1694

CD83 is a marker for mature dendritic cells (DC) generated from peripheral blood mononuclear cells (PBMC)

Authors
Morse, M; Zhou, LJ; Tedder, T; Lyerly, HK; Smith, C
MLA Citation
Morse, M, Zhou, LJ, Tedder, T, Lyerly, HK, and Smith, C. "CD83 is a marker for mature dendritic cells (DC) generated from peripheral blood mononuclear cells (PBMC)." November 15, 1995.
Source
wos-lite
Published In
Blood
Volume
86
Issue
10
Publish Date
1995
Start Page
1279
End Page
1279

Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma.

BACKGROUND: The incidence of lymphoproliferative disease, including B-cell lymphomas (BCL) in patients who have undergone heart or combined heart-lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo. METHODS AND RESULTS: An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor cells in low-dose interleukin-2. Autologous BCL, HLA-mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using 51CrO4 after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at an effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells. CONCLUSIONS: The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV-associated lymphomas.

Authors
DiMaio, JM; Van Trigt, P; Gaynor, JW; Davis, RD; Coveney, E; Clary, BM; Lyerly, HK
MLA Citation
DiMaio, JM, Van Trigt, P, Gaynor, JW, Davis, RD, Coveney, E, Clary, BM, and Lyerly, HK. "Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma." Circulation 92.9 Suppl (November 1, 1995): II202-II205.
PMID
7586409
Source
pubmed
Published In
Circulation
Volume
92
Issue
9 Suppl
Publish Date
1995
Start Page
II202
End Page
II205

Ambulatory surgical management of breast carcinoma using paravertebral block.

OBJECTIVE: The authors describe an initial experience using paravertebral block for ambulatory or short-stay operations for breast cancer. BACKGROUND: Rising hospital costs have focused attention on limiting the length of stay for patients undergoing surgical treatment of breast cancer. Thus far, ambulatory surgery has been limited by side effects and complications of general anesthesia. Paravertebral block offers the potential benefit of effective analgesia, with limited postoperative nausea and vomiting. METHODS: The medical records of the first 15 patients with breast cancer who underwent 16 major operations for the treatment of breast cancer using paravertebral block were reviewed. Patients were either discharged directly from the recovery room or after overnight hospital admission. The effectiveness of anesthesia, surgical outcome, patient satisfaction, and hospital costs are reviewed. RESULTS: Paravertebral block achieved effective anesthesia for cancer operations of the breast and axilla; conversion to general anesthesia or supplementation with local anesthesia was not required. There was one postoperative hemorrhage, there were two seromas, and there was one superficial wound infection. Sensory block persisted for an average of 23 hours. Postoperative pain was effectively controlled, in fact, nine patients required no postoperative narcotic for pain control. Nausea and vomiting transiently afflicted three patients and prompted overnight observation in one patient originally scheduled for immediate discharge. Fourteen patients (93%) rated their experience as "very satisfactory." CONCLUSION: Breast operations for the surgical management of breast cancer using paravertebral block can be performed safely, with great patient satisfaction, and with potential for significant cost savings.

Authors
Weltz, CR; Greengrass, RA; Lyerly, HK
MLA Citation
Weltz, CR, Greengrass, RA, and Lyerly, HK. "Ambulatory surgical management of breast carcinoma using paravertebral block." Ann Surg 222.1 (July 1995): 19-26.
PMID
7618963
Source
pubmed
Published In
Annals of Surgery
Volume
222
Issue
1
Publish Date
1995
Start Page
19
End Page
26

AAV PLASMID - LIPOSOME COMPLEXES FOR THE GENETIC-MODIFICATION OF FRESH PRIMARY TUMOR-CELLS - USE IN TUMOR VACCINATION FOR BREAST-CANCER

Authors
LEBKOWSKI, J; PHILIP, M; LYERLY, K; CLARY, B; BRUNETTE, E; KILINSKI, L; MURUGESH, D; COVENEY, E; OKARMA, TB; PHILIP, R
MLA Citation
LEBKOWSKI, J, PHILIP, M, LYERLY, K, CLARY, B, BRUNETTE, E, KILINSKI, L, MURUGESH, D, COVENEY, E, OKARMA, TB, and PHILIP, R. "AAV PLASMID - LIPOSOME COMPLEXES FOR THE GENETIC-MODIFICATION OF FRESH PRIMARY TUMOR-CELLS - USE IN TUMOR VACCINATION FOR BREAST-CANCER." JOURNAL OF CELLULAR BIOCHEMISTRY (March 10, 1995): 424-424.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1995
Start Page
424
End Page
424

Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis.

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Cytoreductive surgery and intraperitoneal chemotherapy for peritoneal carcinomatosis." Ann Surg 221.2 (February 1995): 123-.
PMID
7857140
Source
pubmed
Published In
Annals of Surgery
Volume
221
Issue
2
Publish Date
1995
Start Page
123

UNTITLED

Authors
LYERLY, HK; MAULT, J
MLA Citation
LYERLY, HK, and MAULT, J. "UNTITLED." ANNALS OF SURGERY 221.2 (February 1995): 207-208.
Source
wos-lite
Published In
Annals of Surgery
Volume
221
Issue
2
Publish Date
1995
Start Page
207
End Page
208

Transmissible agents and the surgeon.

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Transmissible agents and the surgeon." J Am Coll Surg 180.1 (January 1995): 91-92.
PMID
8000663
Source
pubmed
Published In
Journal of The American College of Surgeons
Volume
180
Issue
1
Publish Date
1995
Start Page
91
End Page
92

Gene transfer to the thymus: A means of abrogating the immune response to recombinant adenovirus

Objective: The authors investigated whether adenoviral gene transfer to the thymus could be accomplished in vive and whether immunologic unresponsiveness to recombinant adenovirus could be induced by intrathymic inoculation. Summary Background Data: A major barrier to the clinical application of adenovirus-mediated gene therapy for diseases requiring long- lasting gene expression is the immunogenicity of adenoviral vectors, which limits the duration of its effects. In other experimental models, intrathymic inoculation of foreign proteins or cells has proven to be an effective means to induce immunologic tolerance. Methods: The efficiency of gene transfer to the mouse thymus after direct inoculation of recombinant adenovirus was compared with that of several other vectors. Animals inoculated with adenovirus-infected pancreatic islets into the thymus were tested for unresponsiveness to the virus with a subsequent challenge of adenovirus administered into the liver by intravenous injection. Results: Adenovirus accomplished highly efficient gene transfer to the thymus, unlike plasmid DNA, DNA-liposome complexes, retrovirus, and adeno-associated virus. Adenoviral transgene expression was transient in the thymus of immunocompetent mice but persistent in CD8+ T-cell-deficient and severe combined immunodeficiency (SCID) mice, implicating the role of cytotoxic T lymphocytes in vital clearance. Intrathymic transplantation of syngeneic pancreatic islet cells infected with adenovirus impaired the normal antiviral cytotoxic T-lymphocyte response and prolonged hepatic transgene expression after an intravenous challenge with adenovirus. Conclusions: Recombinant adenovirus accomplishes highly efficient gene transfer to the thymus in vivo. Intrathymic inoculation of adenovirus-infected islets can be used to induce immunologic unresponsiveness to the adenoviral vector and, potentially, to other proteins that it might be engineered to encode.

Authors
DeMatteo, RP; Raper, SE; Ahn, M; Fisher, KJ; Burke, C; Radu, A; Widera, G; Claytor, BR; Barker, CF; Markmann, JF; Simmons, RL; Alexander, JW; Busuttil, RW; Lyerly, K; Flye, MW
MLA Citation
DeMatteo, RP, Raper, SE, Ahn, M, Fisher, KJ, Burke, C, Radu, A, Widera, G, Claytor, BR, Barker, CF, Markmann, JF, Simmons, RL, Alexander, JW, Busuttil, RW, Lyerly, K, and Flye, MW. "Gene transfer to the thymus: A means of abrogating the immune response to recombinant adenovirus." Annals of Surgery 222.3 (1995): 229-242.
PMID
7677454
Source
scival
Published In
Annals of Surgery
Volume
222
Issue
3
Publish Date
1995
Start Page
229
End Page
242

GENE MODIFICATION OF PRIMARY TUMOR-CELLS FOR ACTIVE IMMUNOTHERAPY OF HUMAN BREAST AND OVARIAN-CANCER

Authors
PHILIP, R; BRUNETTE, E; CLARY, B; KILINSKI, L; MURUGESH, D; SORICH, M; YAU, J; LEBKOWSKI, J; LYERLY, HK; PHILIP, M
MLA Citation
PHILIP, R, BRUNETTE, E, CLARY, B, KILINSKI, L, MURUGESH, D, SORICH, M, YAU, J, LEBKOWSKI, J, LYERLY, HK, and PHILIP, M. "GENE MODIFICATION OF PRIMARY TUMOR-CELLS FOR ACTIVE IMMUNOTHERAPY OF HUMAN BREAST AND OVARIAN-CANCER." 1995.
Source
wos-lite
Published In
European Journal of Cancer
Volume
31A
Publish Date
1995
Start Page
77
End Page
77

Immunotherapy of cancer using cytokine gene-modified tumor vaccines.

Distant metastasis is the major cause for therapeutic failures in clinical oncology. Active immunotherapy of patients with low tumor burden would not only contribute to further reduction of the remaining tumor burden to subclinical levels, but it would also establish a constant state of immunity, i.e. immunological memory, that could protect the patient from recurrence of disease. Studies employing rodent tumor models with little or no intrinsic immunogenicity have shown that genitically modified tumor cell preparations consisting of irradiated tumor cells transduced with and expressing cytokines such as IL-2, IL-6, IFN-gamma or GM-CSF were capable of inducing the regression of a preexisting tumor burden and cure animals from their disease. Moreover, in some instances the cured animals have retained immunological memory, as indicated by the fact that such animals have resisted a second challenge with the parental tumor cells. Induction of potent immune responses in tumor bearing animals against non-immunogenic tumors supports the view that active immunization of cancer patients deserves consideration despite lack of demonstrable immunogenicity in many human tumors.

Authors
Gilboa, E; Lyerly, HK; Vieweg, J; Saito, S
MLA Citation
Gilboa, E, Lyerly, HK, Vieweg, J, and Saito, S. "Immunotherapy of cancer using cytokine gene-modified tumor vaccines." Semin Cancer Biol 5.6 (December 1994): 409-417. (Review)
PMID
7703440
Source
pubmed
Published In
Seminars in Cancer Biology
Volume
5
Issue
6
Publish Date
1994
Start Page
409
End Page
417

PATHOGENESIS OF TRANSPLANT-ASSOCIATED B-CELL LYMPHOMAS DIFFERS FROM THOSE ASSOCIATED WITH AIDS

Authors
NG, VL; DIMAIO, JM; HURT, MH; GUNTHEL, CJ; LYERLY, HK; MCGRATH, MS
MLA Citation
NG, VL, DIMAIO, JM, HURT, MH, GUNTHEL, CJ, LYERLY, HK, and MCGRATH, MS. "PATHOGENESIS OF TRANSPLANT-ASSOCIATED B-CELL LYMPHOMAS DIFFERS FROM THOSE ASSOCIATED WITH AIDS." November 15, 1994.
Source
wos-lite
Published In
Blood
Volume
84
Issue
10
Publish Date
1994
Start Page
A611
End Page
A611

GENERATION OF TUMOR-SPECIFIC CYTOTOXIC T-LYMPHOCYTES FOR THE TREATMENT OF POSTTRANSPLANT LYMPHOMA

Authors
DIMAIO, JM; ISENBERG, A; VANTRIGT, P; GAYNOR, JW; DAVIS, RD; COVENEY, E; CLARY, B; LYERLY, HK
MLA Citation
DIMAIO, JM, ISENBERG, A, VANTRIGT, P, GAYNOR, JW, DAVIS, RD, COVENEY, E, CLARY, B, and LYERLY, HK. "GENERATION OF TUMOR-SPECIFIC CYTOTOXIC T-LYMPHOCYTES FOR THE TREATMENT OF POSTTRANSPLANT LYMPHOMA." October 1994.
Source
wos-lite
Published In
Circulation
Volume
90
Issue
4
Publish Date
1994
Start Page
638
End Page
638

T cells or active Epstein-Barr virus infection in the development of lymphoproliferative disease in human B cell-injected severe combined immunodeficient mice.

BACKGROUND: Severe combined immunodeficient (SCID) mice develop Epstein-Barr virus (EBV) containing human lymphoproliferative disease (LPD) tumors when reconstituted with human peripheral blood leukocytes (PBLs) from EBV-seropositive donors, but LPD tumors do not develop in the presence of immunosuppressive agents, such as cyclosporine A or corticosteroids. METHODS: Therefore, LPD development in SCID mice was used as a model to explore the relationship among B cells, T cells, and EBV in vivo. SCID mice were engrafted with PBLs isolated by leukapheresis from a single EBV-seropositive donor. Purified populations of CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) were isolated and engrafted into SCID mice. RESULTS: SCID mice engrafted with purified CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) did not develop LPD. In contrast, mice engrafted with purified B cells developed LPD if they were co-engrafted with purified T cells or if they were inoculated with infectious EBV. CONCLUSIONS: This study confirms the requirement of T cells or active EBV infection in the development of LPD in animals engrafted with B cells latently infected with EBV. A greater understanding of the cellular and viral interactions leading to transformation and malignancy may allow the development of specific interventional therapies for malignancies in the immunosuppressed host.

Authors
Coles, RE; Boyle, TJ; DiMaio, JM; Berend, KR; Via, DF; Lyerly, HK
MLA Citation
Coles, RE, Boyle, TJ, DiMaio, JM, Berend, KR, Via, DF, and Lyerly, HK. "T cells or active Epstein-Barr virus infection in the development of lymphoproliferative disease in human B cell-injected severe combined immunodeficient mice." Ann Surg Oncol 1.5 (September 1994): 405-410.
PMID
7531601
Source
pubmed
Published In
Annals of Surgical Oncology
Volume
1
Issue
5
Publish Date
1994
Start Page
405
End Page
410

Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo.

BACKGROUND: Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. METHODS: Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3CEA-TK) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 10(6) tumor cells consisting of BXPC3 and/or BXPC3CEA-TK cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. RESULTS: All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3CEA-TK cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3CEA-TK engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. CONCLUSIONS: These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.

Authors
DiMaio, JM; Clary, BM; Via, DF; Coveney, E; Pappas, TN; Lyerly, HK
MLA Citation
DiMaio, JM, Clary, BM, Via, DF, Coveney, E, Pappas, TN, and Lyerly, HK. "Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo." Surgery 116.2 (August 1994): 205-213.
PMID
8047987
Source
pubmed
Published In
Surgery
Volume
116
Issue
2
Publish Date
1994
Start Page
205
End Page
213

DIRECT GENE-TRANSFER AND MOLECULAR INTERVENTIONS FOR AIDS AND CANCER

Authors
NABEL, GJ; NABEL, EG; PLAUTZ, GE; LIU, J; YANG, Z; WOFFENDIN, C; GAO, X; HUANG, L; GORDON, D; FOX, B; SHU, S; MALIM, M; CULLEN, B; LYERLY, HK; BOYLE, T; CHANG, A
MLA Citation
NABEL, GJ, NABEL, EG, PLAUTZ, GE, LIU, J, YANG, Z, WOFFENDIN, C, GAO, X, HUANG, L, GORDON, D, FOX, B, SHU, S, MALIM, M, CULLEN, B, LYERLY, HK, BOYLE, T, and CHANG, A. "DIRECT GENE-TRANSFER AND MOLECULAR INTERVENTIONS FOR AIDS AND CANCER." August 1994.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
10
Publish Date
1994
Start Page
S19
End Page
S19

HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer.

Previously, we have reported a correlation between the expression of HER2/neu and sensitivity to HLA-A2-restricted cytotoxic T-cells (CTL) in ovarian cancer. To investigate the role of HER2/neu in human non-small cell lung cancer (NSCLC), we established autologous tumor-specific CTL from tumor-infiltrating lymphocytes of HLA-A2+ HER2/neu+ NSCLC patients. These CTL lines specifically recognized HLA-A2+ HER2/neu+ autologous and allogeneic NSCLC cell lines as well as HLA-A2+ HER2/neu+ heterologous ovarian cancer cell lines. Furthermore, these CTL recognized an overexpressed, HER2/neu-derived peptide. From these results, we conclude that HLA-A2 serves as a restriction element in NSCLC. More importantly, at least one HER2/neu-derived peptide is a tumor-associated antigen in NSCLC and ovarian cancer.

Authors
Yoshino, I; Goedegebuure, PS; Peoples, GE; Parikh, AS; DiMaio, JM; Lyerly, HK; Gazdar, AF; Eberlein, TJ
MLA Citation
Yoshino, I, Goedegebuure, PS, Peoples, GE, Parikh, AS, DiMaio, JM, Lyerly, HK, Gazdar, AF, and Eberlein, TJ. "HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer." Cancer Res 54.13 (July 1, 1994): 3387-3390.
PMID
7912166
Source
pubmed
Published In
Cancer Research
Volume
54
Issue
13
Publish Date
1994
Start Page
3387
End Page
3390

Laparoscopic ileostomy and colostomy.

OBJECTIVE: The technical features of laparoscopic ileostomy and colostomy are described. SUMMARY BACKGROUND DATA: A diverting ileostomy or colostomy can be performed with minimal trauma by laparoscopic techniques. This is distinct from the complex laparoscopic and laparoscopic-assisted resections of small and large bowel. To date the technical features of creating a diverting ileostomy or colostomy have not been emphasized sufficiently. METHODS: Standard laparoscopic techniques are used to create a pneumoperitoneum. After mobilization of the ileum or colon, a stoma is made on the abdominal wall. A trocar is introduced at the site where the stoma is located, thus reducing the technical problems associated with creating and maturing a stoma while the abdomen is insufflated. RESULTS: This approach obviates the need for a laparotomy while creating an ileostomy or colostomy. The technical features of creating a double-barrel ostomy, an end-ostomy with a stapled distal limb, and a loop ostomy are described. The postoperative recovery is prompt with a rapid return of intestinal function and early discharge from the hospital. CONCLUSIONS: Laparoscopic ileostomy and colostomy are straightforward procedures that reduce postoperative discomfort and ileus, and reduce the length of hospital stay.

Authors
Lyerly, HK; Mault, JR
MLA Citation
Lyerly, HK, and Mault, JR. "Laparoscopic ileostomy and colostomy." Ann Surg 219.3 (March 1994): 317-322.
PMID
8147614
Source
pubmed
Published In
Annals of Surgery
Volume
219
Issue
3
Publish Date
1994
Start Page
317
End Page
322

Seventeenth Sir Peter Freyer memorial lecture and surgical symposium: September 23rd & 24th, 1993

Authors
O Broin, E; Donohoe, J; Mealy, K; Kerin, M; Gillen, P; Tanner, WA; Keane, FBV; McCarthy, P; Rubesin, S; Herlinger, H; Laufer, I; Caldwell, MTP; Lawlor, P; Byrne, PJ; Walsh, TN; Hennessy, TPJ; Curran, AJ; Gormley, P; Barry, K; McGuire, M; Marks, P; Asad, AS; Lane, B; Browne, HI; Keeling, P; Barry, MK; Yeo, CJ; Sauter, PK; Lillemoe, KD; Pitt, HA; Cameron, JL; Sostre, S; O Donovan, DA; Kelly, CJ; Bouchier-Hayes, DM; Redmond, HP; Burke, P; Monkhouse, WS; Burke, J; Willia, N; Gorey, T; Afdhal, NH et al.
MLA Citation
O Broin, E, Donohoe, J, Mealy, K, Kerin, M, Gillen, P, Tanner, WA, Keane, FBV, McCarthy, P, Rubesin, S, Herlinger, H, Laufer, I, Caldwell, MTP, Lawlor, P, Byrne, PJ, Walsh, TN, Hennessy, TPJ, Curran, AJ, Gormley, P, Barry, K, McGuire, M, Marks, P, Asad, AS, Lane, B, Browne, HI, Keeling, P, Barry, MK, Yeo, CJ, Sauter, PK, Lillemoe, KD, Pitt, HA, Cameron, JL, Sostre, S, O Donovan, DA, Kelly, CJ, Bouchier-Hayes, DM, Redmond, HP, Burke, P, Monkhouse, WS, Burke, J, Willia, N, Gorey, T, and Afdhal, NH et al. "Seventeenth Sir Peter Freyer memorial lecture and surgical symposium: September 23rd & 24th, 1993." January 1, 1994.
Source
scopus
Published In
Irish Journal of Medical Science
Volume
163
Issue
4
Publish Date
1994
Start Page
139
End Page
167
DOI
10.1007/BF02967221

Sabiston Essentials of Surgery

This 2nd Edition presents the key features necessary for basic surgical practice.

Authors
Sabiston, DC
MLA Citation
Sabiston, DC. Sabiston Essentials of Surgery. Saunders, 1994.
Source
google-books
Publish Date
1994

RETROVIRAL VECTOR-MEDIATED GAMMA-IFN GENE-TRANSFER TO TUMOR-CELLS FOR CANCER-THERAPY

Authors
GANGAVALLI, R; MCCALLISTER, T; NAYAK, S; DILLMAN, R; ROSENBLATT, J; SEEGER, R; BRENNER, M; COZE, C; LYERLY, K; SIEGLER, H; JOLLY, D; BARBER, J
MLA Citation
GANGAVALLI, R, MCCALLISTER, T, NAYAK, S, DILLMAN, R, ROSENBLATT, J, SEEGER, R, BRENNER, M, COZE, C, LYERLY, K, SIEGLER, H, JOLLY, D, and BARBER, J. "RETROVIRAL VECTOR-MEDIATED GAMMA-IFN GENE-TRANSFER TO TUMOR-CELLS FOR CANCER-THERAPY." JOURNAL OF CELLULAR BIOCHEMISTRY (1994): 114-114.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1994
Start Page
114
End Page
114

Cytomegalovirus sialadenitis in patients with the acquired immunodeficiency syndrome: a potential diagnostic pitfall with fine-needle aspiration cytology.

We report three cases of cytomegalovirus (CMV) sialadenitis which presented as parotid gland nodules in patients infected with the human immunodeficiency virus. While CMV is known to widely infect patients with the acquired immunodeficiency syndrome (AIDS), we are aware of only a single report of CMV sialadenitis in a patient with AIDS (Pialoux et al.: Rev Infect Dis 1991;13:338). Utilizing fine-needle aspiration (FNA) cytology as the initial investigative modality, two cases were correctly diagnosed preoperatively while the third case displayed atypical features and was interpreted erroneously as carcinoma leading to surgical intervention. Upon review of these cases of CMV sialadenitis, the characteristic intranuclear inclusions are best identified with Papanicolaou (Pap) staining. CMV sialadenitis should be considered in the differential diagnosis of painless salivary gland enlargement in patients with AIDS. We believe this lesion can be diagnosed preoperatively with FNA and the interpretation is aided by evaluating both Pap- and Giemsa-stained material.

Authors
Wax, TD; Layfield, LJ; Zaleski, S; Bhargara, V; Cohen, M; Lyerly, HK; Fisher, SR
MLA Citation
Wax, TD, Layfield, LJ, Zaleski, S, Bhargara, V, Cohen, M, Lyerly, HK, and Fisher, SR. "Cytomegalovirus sialadenitis in patients with the acquired immunodeficiency syndrome: a potential diagnostic pitfall with fine-needle aspiration cytology." Diagn Cytopathol 10.2 (1994): 169-172.
PMID
8187600
Source
pubmed
Published In
Diagnostic Cytopathology
Volume
10
Issue
2
Publish Date
1994
Start Page
169
End Page
172

Sylvester O'halloran surgical scientific meeting - Proceedings of meeting held march 11th & 12th, 1994 in the John Holland theatre, university of Limerick.

Authors
Barry, MC; Burke, P; Joyce, WP; Sheehan, S; Broe, P; Bouchier-Hayes, D; Mccollum, PT; Holdsworth, RI; Stonebridge, PA; Belch, JJ; Osuilleabhain, C; Waldron, D; Hehir, D; Odonnell, JA; Brady, MP; Kelly, J; Odonnell, J; Morasch, MD; Couse, NF; Colgan, MP; Moore, DJ; Shanik, GD; Russell, JD; Odwyer, TP; Russell, J; Walsh, M; Lennon, GM; Sweeney, P; Grainger, R; Mcdermott, TED; Thornhill, JA; Butler, MR; Vashisht, R; Koppikar, M; Rogers, HS; Stokes, MA; Carroll, T; Regan, MC; Fitzpatrick, JM et al.
MLA Citation
Barry, MC, Burke, P, Joyce, WP, Sheehan, S, Broe, P, Bouchier-Hayes, D, Mccollum, PT, Holdsworth, RI, Stonebridge, PA, Belch, JJ, Osuilleabhain, C, Waldron, D, Hehir, D, Odonnell, JA, Brady, MP, Kelly, J, Odonnell, J, Morasch, MD, Couse, NF, Colgan, MP, Moore, DJ, Shanik, GD, Russell, JD, Odwyer, TP, Russell, J, Walsh, M, Lennon, GM, Sweeney, P, Grainger, R, Mcdermott, TED, Thornhill, JA, Butler, MR, Vashisht, R, Koppikar, M, Rogers, HS, Stokes, MA, Carroll, T, Regan, MC, and Fitzpatrick, JM et al. "Sylvester O'halloran surgical scientific meeting - Proceedings of meeting held march 11th & 12th, 1994 in the John Holland theatre, university of Limerick." 1994.
Source
scival
Published In
Irish Journal of Medical Science
Volume
163
Issue
11
Publish Date
1994
Start Page
517
End Page
532
DOI
10.1007/BF02967098

Irish society for gastroenterology - Abstracts of Poster Presentations presented at the Irish Society for Gastroenterology, James Connolly Memorial Hospital, Blanchardstown on November 26th and 27th, 1993

Authors
Mealy, K; Adeyoju, A; O'Nullain, E; Smyth, H; Keane, FBV; Reen, D; Tanner, A; Wang, JH; Redmond, HP; Watson, RWG; Duggen, S; Boucher-Hayes, D; Casey, M; Stevens, FM; Bruzzi, J; El-Magbri, AA; Stevens, FM; McCarthy, CF; Egan, LJ; Johnston, J; Walsh, S; Murphy, RP; O'Gorman, T; Headon, DR; Connolly, CE; Johnston, S; Tham, TCK; Watson, RGP; O'Donnell, LJD; Battistini, B; Warner, TD; Fournier, A; Farthing, MJG; Vane, RJ; Skelly, MM; Mulcahy, HE; O'Donoghue, DP; McDermott, EWM; Khalifa, KA et al.
MLA Citation
Mealy, K, Adeyoju, A, O'Nullain, E, Smyth, H, Keane, FBV, Reen, D, Tanner, A, Wang, JH, Redmond, HP, Watson, RWG, Duggen, S, Boucher-Hayes, D, Casey, M, Stevens, FM, Bruzzi, J, El-Magbri, AA, Stevens, FM, McCarthy, CF, Egan, LJ, Johnston, J, Walsh, S, Murphy, RP, O'Gorman, T, Headon, DR, Connolly, CE, Johnston, S, Tham, TCK, Watson, RGP, O'Donnell, LJD, Battistini, B, Warner, TD, Fournier, A, Farthing, MJG, Vane, RJ, Skelly, MM, Mulcahy, HE, O'Donoghue, DP, McDermott, EWM, and Khalifa, KA et al. "Irish society for gastroenterology - Abstracts of Poster Presentations presented at the Irish Society for Gastroenterology, James Connolly Memorial Hospital, Blanchardstown on November 26th and 27th, 1993." 1994.
Source
scival
Published In
Irish Journal of Medical Science
Volume
163
Issue
1
Publish Date
1994
Start Page
37
End Page
47
DOI
10.1007/BF02943012

In vitro and in vivo kinetics of recombinant vaccinia virus cancer-gene therapy

Background. Gene therapy of cancer is a promising therapeutic modality. Recombinant vaccinia viruses (RecVV), engineered to produce cytokines, may be effective in this area. This study's purpose was to investigate the kinetics of RecVV infection, measuring protein production and in vivo viral growth pattern. Methods. RecVV were constructed by homologous recombination, encoding murine interleukin-2 (mIL-2). After tumor cell infection, mIL-2 production was measured in vitro. Tumor-bearing and naive hosts were inoculated with RecVV and wild type vaccinia. Livers, spleens, and (where applicable) tumors were sequentially harvested, and tissue viral levels were measured. Results. Infected tumor cells made high levels of mIL-2 after infection with RecVV encoding for this cytokine. Naive mice were able to clear recombinant but not wild type VV from their livers and spleens by days 3 and 5, respectively. Tumor-bearing animals had persistent RecVV titers in the tumor tissue at day 8. Conclusions. RecVV can infect tumor cells, causing the production of a large amount of foreign protein but are attenuated relative to wild type virus in the murine host.

Authors
Whitman, ED; Tsung, K; Paxson, J; Norton, JA; Shaked, A; Lyerly, HK
MLA Citation
Whitman, ED, Tsung, K, Paxson, J, Norton, JA, Shaked, A, and Lyerly, HK. "In vitro and in vivo kinetics of recombinant vaccinia virus cancer-gene therapy." Surgery 116.2 (1994): 183-188.
PMID
8047984
Source
scival
Published In
Surgery
Volume
116
Issue
2
Publish Date
1994
Start Page
183
End Page
188

Gene delivery systems in surgery.

Increased understanding of the genetic basis of human disease has led to a number of potential gene-based therapies for various medical and surgical disorders. The development of efficient methods for delivering genes to mammalian cells in vitro has increased the potential clinical utility of gene-based therapies; however, a major focus of research has been more efficient delivery to appropriate target cells, in vivo as well as in vitro, to establish gene therapy as an effective clinical modality for common disorders. Despite substantial progress, a number of critical technical issues to enhance and optimize not only gene transfer but also gene expression must be resolved. These future technological developments will be essential for the widespread clinical implementation of gene-based therapy.

Authors
Lyerly, HK; DiMaio, JM
MLA Citation
Lyerly, HK, and DiMaio, JM. "Gene delivery systems in surgery." Arch Surg 128.11 (November 1993): 1197-1206. (Review)
PMID
8239982
Source
pubmed
Published In
Archives of Surgery
Volume
128
Issue
11
Publish Date
1993
Start Page
1197
End Page
1206

Phenotypic and functional consequences of herpesvirus saimiri infection of human CD8+ cytotoxic T lymphocytes.

Herpesvirus saimiri (HVS) was used to infect and transform human CD8+ cytotoxic T lymphocytes (CTL), and the phenotypic and functional consequences of HVS infection of CD8+ T lymphocytes were investigated. HVS-transformed CTL no longer require antigen restimulation yet maintain their phenotype and HLA-restricted cytolytic function and specificity. The ability of HVS to transform CTL may have an important role in the functional analysis of human antigen-specific CTL.

Authors
Berend, KR; Jung, JU; Boyle, TJ; DiMaio, JM; Mungal, SA; Desrosiers, RC; Lyerly, HK
MLA Citation
Berend, KR, Jung, JU, Boyle, TJ, DiMaio, JM, Mungal, SA, Desrosiers, RC, and Lyerly, HK. "Phenotypic and functional consequences of herpesvirus saimiri infection of human CD8+ cytotoxic T lymphocytes." J Virol 67.10 (October 1993): 6317-6321.
PMID
8396687
Source
pubmed
Published In
Journal of virology
Volume
67
Issue
10
Publish Date
1993
Start Page
6317
End Page
6321

Adoptive transfer of cytotoxic T lymphocytes for the treatment of transplant-associated lymphoma.

BACKGROUND: Immunocompromised organ transplant recipients have a high incidence of B cell lymphomas (BCL). Severe combined immunodeficient (SCID) mice develop human BCL when engrafted with Epstein-Barr virus (EBV) transformed and immortalized B lymphoblastoid cell lines (BLCL). Because a lack of effective EBV-specific cytotoxic T lymphocytes (EBV-CTL) is thought to lead to lymphoma development, the SCID mouse model was used to determine the relationship between EBV-infected B cells and EBV-specific CTL in BCL development in vivo. METHODS: EBV-CTL were generated by in vitro stimulation of peripheral blood leukocytes with autologous BLCL. CD8+ CTL were isolated from CTL populations by depletion of CD4+ cells. SCID mice were engrafted with BLCL, EBV-CTL were adoptively transferred into engrafted SCID mice either immediately or 7 days after engraftment, and the animals were monitored for the development of BCL. Statistical significance was determined by the log rank test. RESULTS: SCID mice engrafted with BLCL rapidly developed BCL (mean, 20 days). SCID mice engrafted with BLCL and human leukocyte antigen-identical EBV-CTL or CD8+ EBV-CTL had a significant delay in BCL development (p < 0.05), whereas some mice did not develop BCL. In contrast, human leukocyte antigen-nonidentical EBV-CTL did not significantly delay BCL development. CONCLUSIONS: This study showed the role of EBV-CTL in inhibiting the development of BCL. A greater understanding of the cellular and viral interactions leading to B-cell transformation and malignancy may allow the development of specific interventional therapies in patients who have received immunosuppressants.

Authors
Boyle, TJ; Berend, KR; DiMaio, JM; Coles, RE; Via, DF; Lyerly, HK
MLA Citation
Boyle, TJ, Berend, KR, DiMaio, JM, Coles, RE, Via, DF, and Lyerly, HK. "Adoptive transfer of cytotoxic T lymphocytes for the treatment of transplant-associated lymphoma." Surgery 114.2 (August 1993): 218-225.
PMID
8393595
Source
pubmed
Published In
Surgery
Volume
114
Issue
2
Publish Date
1993
Start Page
218
End Page
225

TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION

Authors
MALIM, MH; FREIMUTH, WW; LIU, J; BOYLE, TJ; LYERLY, HK; CULLEN, BR; NABEL, GJ
MLA Citation
MALIM, MH, FREIMUTH, WW, LIU, J, BOYLE, TJ, LYERLY, HK, CULLEN, BR, and NABEL, GJ. "TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION." June 1993.
Source
wos-lite
Published In
Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association
Volume
6
Issue
6
Publish Date
1993
Start Page
669
End Page
669

DIRECT GENE-TRANSFER AND MOLECULAR INTERVENTIONS FOR AIDS AND CANCER

Authors
NABEL, GJ; NABEL, EG; PLAUTZ, GE; LIU, J; YANG, Z; WOFFENDIN, C; GAO, X; HUANG, L; GORDON, D; FOX, B; SHU, S; MALIM, M; CULLEN, B; LYERLY, HK; BOYLE, T; CHANG, A
MLA Citation
NABEL, GJ, NABEL, EG, PLAUTZ, GE, LIU, J, YANG, Z, WOFFENDIN, C, GAO, X, HUANG, L, GORDON, D, FOX, B, SHU, S, MALIM, M, CULLEN, B, LYERLY, HK, BOYLE, T, and CHANG, A. "DIRECT GENE-TRANSFER AND MOLECULAR INTERVENTIONS FOR AIDS AND CANCER." March 29, 1993.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1993
Start Page
185
End Page
185

Retroviral gene transduction of circulating progenitor cells in patients with metastatic breast cancer.

The use of somatic gene therapy for the treatment of breast cancer has many potential applications. Because chemotherapeutic protocols for breast cancer are commonly limited by bone marrow toxicity, transduction of genes into pleuripotent stem cells may allow the generation and maintenance of immune responses in the presence of lymphocytotoxic agents. The practical utility of stem cell isolation and transduction would be enhanced if stem cells circulating in the peripheral blood could be isolated in patients, however this approach has been limited by the small numbers of such cells in the circulation. In these studies, recombinant granulocyte colony stimulating factor (G-CSF) was administered to patients with metastatic breast cancer to increase the number of circulating stem cells. Stem cells in the peripheral blood were then isolated and a retroviral vector (LXSN) was used to transduce the neomycin phosphotransferase gene into these cells. Gene transduction was demonstrated by resistance to the toxic effects of a neomycin analog (G418) and the detection of retroviral DNA from transduced cells. A practical method of transfer of exogenous genes into the circulating pleuripotent stem cells of patients with metastatic breast cancer is documented by these experiments. Application of these findings may allow the generation of cells resistant to anti-neoplastic agents or unique lymphoid effector cells with potent immune functions for the treatment of patients with metastatic breast cancer.

Authors
Coles, RE; Boyle, TJ; Kurtzberg, J; Stewart, A; Peters, WP; Lyerly, HK
MLA Citation
Coles, RE, Boyle, TJ, Kurtzberg, J, Stewart, A, Peters, WP, and Lyerly, HK. "Retroviral gene transduction of circulating progenitor cells in patients with metastatic breast cancer." Surg Oncol 2.1 (1993): 1-6.
PMID
8252190
Source
pubmed
Published In
Surgical Oncology
Volume
2
Issue
1
Publish Date
1993
Start Page
1
End Page
6

Stable expression of transdominant Rev protein in human T cells inhibits human immunodeficiency virus replication.

The human immunodeficiency virus (HIV) Rev protein is essential for viral structural protein expression (Gag, Pol, and Env) and, hence, for viral replication. In transient transfection assays, mutant forms of Rev have been identified that inhibit wild-type Rev activity and therefore suppress viral replication. To determine whether such transdominant Rev proteins could provide long-term protection against HIV infection without affecting T cell function, T leukemia cell lines were stably transduced with a retroviral vector encoding a transdominant mutant of the Rev protein, M10. While all the M10-expressing cell lines remained infectable by HIV-1, these same cells failed to support a productive replication cycle when infected with a cloned isolate of HIV-1. In addition, two out of three M10-expressing CEM clones were also resistant to highly productive infection by a heterogeneous HIV-1 pool. Expression of M10 did not affect induction of HIV transcription mediated by the kappa B regulatory element or Tat. Importantly, constitutive expression of Rev M10 did not alter the secretion of interleukin 2 in response to mitogen stimulation of EL-4 and Jurkat cells. The inhibition of HIV infection in cells stably expressing a transdominant Rev protein, in the absence of any deleterious effect on T cell function, suggests that such a strategy could provide a therapeutic effect in the T lymphocytes of acquired immunodeficiency syndrome patients.

Authors
Malim, MH; Freimuth, WW; Liu, J; Boyle, TJ; Lyerly, HK; Cullen, BR; Nabel, GJ
MLA Citation
Malim, MH, Freimuth, WW, Liu, J, Boyle, TJ, Lyerly, HK, Cullen, BR, and Nabel, GJ. "Stable expression of transdominant Rev protein in human T cells inhibits human immunodeficiency virus replication." J Exp Med 176.4 (October 1, 1992): 1197-1201.
PMID
1402661
Source
pubmed
Published In
The Journal of Experimental Medicine
Volume
176
Issue
4
Publish Date
1992
Start Page
1197
End Page
1201

TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION

Authors
MALIM, MH; FREIMUTH, WW; LIU, J; BOYLE, TJ; LYERLY, HK; CULLEN, BR; NABEL, GJ
MLA Citation
MALIM, MH, FREIMUTH, WW, LIU, J, BOYLE, TJ, LYERLY, HK, CULLEN, BR, and NABEL, GJ. "TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION." October 1992.
Source
wos-lite
Published In
Clinical Research
Volume
40
Issue
3
Publish Date
1992
Start Page
A701
End Page
A701

Derivation of a biologically contained replication system for human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV-1) proviral mutants that lack viral regulatory genes are unable to replicate unless rescued by complementation in trans. Structurally intact virus can be produced by infecting recombinant cell lines expressing the deficient genes. A HIV-1 mutant functionally defective in tat and rev (vIIIB delta Tat/Rev), which replicates only in a recombinant T-cell line expressing tat and rev (CEMTART), is described in this report. Infection of the CEMTART cell line with vIIIB delta Tat/Rev permits the complete HIV-1 life cycle, including cytopathology, decreased expression of CD4, and production of viral structural proteins, to be biologically contained. Culture supernatants from infected CEMTART contain virus that is able to replicate only in uninfected CEMTART. No reversion of vIIIB delta Tat/Rev to wild-type HIV-1 was observed as measured either by sequencing proviral vIIIB delta Tat/Rev or by detecting the ability of vIIIB delta Tat/Rev to replicate in CEM or activated CD4-bearing T lymphocytes. Defective HIV-1 mutants produced by trans complementation of essential genes permit infection and analysis of defined genotypes on cellular function and phenotype. Authentic HIV-1 structural proteins and infected cells can be prepared in mass, and agents that interfere with the HIV-1 life cycle can be studied on a large scale with minimum risk of exposing workers to virulent HIV-1.

Authors
Chen, H; Boyle, TJ; Malim, MH; Cullen, BR; Lyerly, HK
MLA Citation
Chen, H, Boyle, TJ, Malim, MH, Cullen, BR, and Lyerly, HK. "Derivation of a biologically contained replication system for human immunodeficiency virus type 1." Proc Natl Acad Sci U S A 89.16 (August 15, 1992): 7678-7682.
PMID
1502183
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
89
Issue
16
Publish Date
1992
Start Page
7678
End Page
7682

Human B-cell lymphoma in severe combined immunodeficient mice after active infection with Epstein-Barr virus.

BACKGROUND: B-cell lymphomas (BCL) occur with increased frequency in immunosuppressed patients. BCL develop in severe combined immunodeficient (SCID) mice after engraftment with human peripheral blood leukocytes (PBL; hu-PBL-SCID mice) and infection with Epstein-Barr virus (EBV). The contributions of latent and active EBV infection to BCL development, the potential enhancing effects of immunosuppressive therapy, and inhibitory effects of antiviral therapy on the development of BCL in this model were studied. METHODS: SCID mice were engrafted with PBL from EBV-seropositive donors (latent infection), PBL from EBV-seronegative donors followed by infection with EBV (active infection), PBL from EBV-seropositive donors followed by infection with EBV (latent plus active infection), or EBV-transformed B-lymphoblastoid cells and monitored for the development of BCL. Hu-PBL-SCID mice were treated with the immunosuppressive agents cyclosporine or methylprednisolone or the antiviral agents acyclovir or ganciclovir. RESULTS: Tumors developing in hu-PBL-SCID mice were high-grade lymphomas of human B-cell origin and contained EBV-DNA. BCL developed in 70% of mice 11 to 14 weeks after latent infection. BCL developed after 4 to 7 weeks in all hu-PBL-SCID mice after active infection. Treatment with cyclosporine or methylprednisolone had no effect on BCL development after active infection, but inhibited rather than enhanced the development of BCL in latently infected mice. Ganciclovir, but not acyclovir, inhibited BCL development after active infection. CONCLUSIONS: The hu-PBL-SCID mouse provides an in vivo model of BCL associated with immunosuppression. Active EBV infection results in the rapid development of BCL in this model even when latently infected B cells are present. Inhibition of BCL development in latently infected hu-PBL-SCID mice by immunosuppressive therapy may reflect inhibition of a T-cell/B-cell interaction necessary for B-cell activation. Inhibition of BCL development by granciclovir suggests a possible role for this agent in the management of BCL associated with immunosuppression.

Authors
Boyle, TJ; Tamburini, M; Berend, KR; Kizilbash, AM; Borowitz, MJ; Lyerly, HK
MLA Citation
Boyle, TJ, Tamburini, M, Berend, KR, Kizilbash, AM, Borowitz, MJ, and Lyerly, HK. "Human B-cell lymphoma in severe combined immunodeficient mice after active infection with Epstein-Barr virus." Surgery 112.2 (August 1992): 378-386.
PMID
1322566
Source
pubmed
Published In
Surgery
Volume
112
Issue
2
Publish Date
1992
Start Page
378
End Page
386

Identification of envelope V3 loop as the major determinant of CD4 neutralization sensitivity of HIV-1.

Laboratory isolates of human immunodeficiency virus type-1 (HIV-1) such as HTLV-IIIB are generally T cell line-tropic and highly sensitive to neutralization by soluble CD4 (sCD4), a potential antiviral agent that is undergoing clinical trial. However, many primary HIV-1 isolates are macrophage-tropic and sCD4-resistant. Envelope V3 loop sequences derived from primary HIV-1 isolates were sufficient to confer on HTLV-IIIB not only the tissue tropism but also the degree of sCD4 neutralization resistance characteristic of their HIV-1 strains of origin. Single amino acid changes in the V3 loop enhanced sCD4 resistance by up to tenfold. These observations suggest that the tissue tropism and sCD4 neutralization sensitivity of HIV-1 isolates are regulated by similar mechanisms.

Authors
Hwang, SS; Boyle, TJ; Lyerly, HK; Cullen, BR
MLA Citation
Hwang, SS, Boyle, TJ, Lyerly, HK, and Cullen, BR. "Identification of envelope V3 loop as the major determinant of CD4 neutralization sensitivity of HIV-1." Science 257.5069 (July 24, 1992): 535-537.
PMID
1636088
Source
pubmed
Published In
Science
Volume
257
Issue
5069
Publish Date
1992
Start Page
535
End Page
537

PH-INDEPENDENT HIV-1 ENTRY INTO MACROPHAGE

Authors
BOYLE, TJ; HWANG, SS; CHEN, H; TAMBURINI, M; CULLEN, BR; LYERLY, HK
MLA Citation
BOYLE, TJ, HWANG, SS, CHEN, H, TAMBURINI, M, CULLEN, BR, and LYERLY, HK. "PH-INDEPENDENT HIV-1 ENTRY INTO MACROPHAGE." May 1992.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
8
Issue
5
Publish Date
1992
Start Page
920
End Page
920

THE ENVELOPE V3 LOOP IS THE PRIMARY DETERMINANT OF CELL TROPISM IN HIV-1

Authors
HWANG, SS; BOYLE, TJ; LYERLY, HK; CULLEN, BR
MLA Citation
HWANG, SS, BOYLE, TJ, LYERLY, HK, and CULLEN, BR. "THE ENVELOPE V3 LOOP IS THE PRIMARY DETERMINANT OF CELL TROPISM IN HIV-1." May 1992.
Source
wos-lite
Published In
AIDS Research and Human Retroviruses
Volume
8
Issue
5
Publish Date
1992
Start Page
867
End Page
867

TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION

Authors
MALIM, MH; FREIMUTH, WW; LIU, J; BOYLE, TJ; LYERLY, HK; CULLEN, BR; NABEL, GJ
MLA Citation
MALIM, MH, FREIMUTH, WW, LIU, J, BOYLE, TJ, LYERLY, HK, CULLEN, BR, and NABEL, GJ. "TRANSDOMINANT REV PROTEIN INHIBITS HIV REPLICATION WITHOUT AFFECTING T-CELL FUNCTION." April 1992.
Source
wos-lite
Published In
Clinical Research
Volume
40
Issue
2
Publish Date
1992
Start Page
A253
End Page
A253

Effects of cyclosporine on human B-cell lymphoma development in vivo.

Cyclosporine (CsA) is a potent immunosuppressive agent primarily affecting T-lymphocyte function. Patients receive CsA following organ transplantation to prevent rejection. These patients are at high risk for developing Epstein-Barr virus (EBV)-induced lymphoproliferative disease (LPD) or B-cell lymphoma (BCL). Severe Combined Immunodeficient (SCID) mice reconstituted with human peripheral blood leukocytes (PBL) develop fatal B-cell lymphomas of human origin following latent or active infection with EBV. This model was utilized to determine the role of CsA in the development of human BCL. SCID mice were reconstituted with PBL, latently or actively infected with EBV, and treated with CsA. Following active EBV infection, mice developed human BCL with or without CsA treatment. In contrast, treatment with CsA prevented the development of BCL in mice latently infected with EBV. This suggests a T-cell interaction with latently infected B-cells which is perturbed by CsA. Further understanding of this interaction and the occurrence of human BCL may allow the development of strategies to prevent, detect, or treat malignancies associated with immunosuppression.

Authors
Boyle, TJ; Coles, RE; Kizilbash, AM; Lyerly, HK
MLA Citation
Boyle, TJ, Coles, RE, Kizilbash, AM, and Lyerly, HK. "Effects of cyclosporine on human B-cell lymphoma development in vivo." Surg Oncol 1.1 (February 1992): 79-86.
PMID
1341239
Source
pubmed
Published In
Surgical Oncology
Volume
1
Issue
1
Publish Date
1992
Start Page
79
End Page
86

The Handbook of Surgical Intensive Care Practices of the Surgical Residents at the Duke University Medical Center

Authors
Lyerly, HK; Gaynor, JW
MLA Citation
Lyerly, HK, and Gaynor, JW. The Handbook of Surgical Intensive Care Practices of the Surgical Residents at the Duke University Medical Center. Mosby Incorporated, 1992.
Source
google-books
Publish Date
1992

Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1.

Cells of the monocyte-macrophage lineage are targets for human immunodeficiency virus-1 (HIV-1) infection in vivo. However, many laboratory strains of HIV-1 that efficiently infect transformed T cell lines replicate poorly in macrophages. A 20-amino acid sequence from the macrophage-tropic BaL isolate of HIV-1 was sufficient to confer macrophage tropism on HTLV-IIIB, a T cell line--tropic isolate. This small sequence element is in the V3 loop, the envelope domain that is the principal neutralizing determinant of HIV-1. Thus, the V3 loop not only serves as a target of the host immune response but is also pivotal in determining HIV-1 tissue tropism.

Authors
Hwang, SS; Boyle, TJ; Lyerly, HK; Cullen, BR
MLA Citation
Hwang, SS, Boyle, TJ, Lyerly, HK, and Cullen, BR. "Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1." Science 253.5015 (July 5, 1991): 71-74.
PMID
1905842
Source
pubmed
Published In
Science
Volume
253
Issue
5015
Publish Date
1991
Start Page
71
End Page
74

Surgical treatment of chronic pulmonary embolism.

Authors
Lyerly, HK; Sabiston, DC
MLA Citation
Lyerly, HK, and Sabiston, DC. "Surgical treatment of chronic pulmonary embolism." Annu Rev Med 42 (1991): 507-517. (Review)
PMID
2035991
Source
pubmed
Published In
Annual Review of Medicine
Volume
42
Publish Date
1991
Start Page
507
End Page
517
DOI
10.1146/annurev.me.42.020191.002451

Alterations in antibody-dependent cellular cytotoxicity during the course of HIV-1 infection. Humoral and cellular defects.

HIV-1-specific cell-mediated cytotoxicity (CMC) is a form of antibody-dependent cellular cytotoxicity (ADCC) in which HIV-1-specific antibodies arm NK cells directly to become cytotoxic for targets bearing HIV-1 antigenic determinants. This non-MHC-restricted cytotoxic activity is present in early stages of disease and declines markedly with disease progression. To understand the cellular and humoral factors contributing to the reduction in this activity, the conditions under which maximal arming of cells occurs was examined in vitro. With the use of a large patient cohort, a strong positive correlation was found between the capacity of a serum to direct lysis in standard ADCC assays and its ability to arm NK cells. Patients with minimal HIV-1-specific ADCC-directing antibodies exhibited low levels of CMC and were unable to arm normal effector cells in vitro. The lack of sufficient ADCC-directing antibodies was found to be one cause of defective CMC in some patients. Unlike asymptomatics, only a weak positive correlation was found between arming and ADCC with sera from AIDS patients, indicating that a factor other than absolute HIV-1 specific antibody titer was responsible for decreased CMC in this patient population. Another group of patients was found to have diminished CMC despite the presence of antibodies in the serum that were fully capable of arming normal effector cells to become cytotoxic for gp120-expressing targets. When compared with those of normal individuals, lymphocytes from seropositive patients mediated significantly reduced levels of cytotoxicity in ADCC and arming assays with the use of a high titered HIV-1-specific serum. In both assay systems, the magnitude and frequency of dysfunction in antibody-dependent cytolysis was found to be greater among AIDS patients than among asymptomatic individuals. The demonstration of both cellular and humoral defects in the ability of seropositive individuals to manifest ADCC reactivities strongly suggests that HIV-1 infection may significantly compromise the effectiveness of this potentially important cytolytic reactivity in vivo.

Authors
Tyler, DS; Stanley, SD; Nastala, CA; Austin, AA; Bartlett, JA; Stine, KC; Lyerly, HK; Bolognesi, DP; Weinhold, KJ
MLA Citation
Tyler, DS, Stanley, SD, Nastala, CA, Austin, AA, Bartlett, JA, Stine, KC, Lyerly, HK, Bolognesi, DP, and Weinhold, KJ. "Alterations in antibody-dependent cellular cytotoxicity during the course of HIV-1 infection. Humoral and cellular defects." J Immunol 144.9 (May 1, 1990): 3375-3384.
PMID
2329275
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
144
Issue
9
Publish Date
1990
Start Page
3375
End Page
3384

Measurement of direct and indirect forms of anti-HIV-1 ADCC: implications for other retroviral disease.

Among the varied cytotoxic immune reactivities elicited as a result of HIV-1 infection are two forms of non-MHC restricted cytotoxicity--namely, indirect and direct ADCC. Since these reactivities are directed at both HIV-1 infected as well as gp120 coated targets, there is a potential for anti-HIV-1 ADCC to play both a beneficial as well as a pathogenic role in the natural history of HIV-1 disease. Resolution of these issues will be of great importance to the development of future preventive and interventive therapeutic strategies for AIDS. The direct and indirect forms of ADCC described herein are, most probably, not unique to HIV-1. In theory, any viral disease, retroviral or otherwise, in which high titers of anti-envelope antibodies persist in an environment rich in Fc-receptor bearing effector NK/K cells would be likely to have some component of direct ADCC as part of the host anti-viral response. With this in mind it is imperative that those researchers involved in characterizing cellular anti-viral cytotoxicities do not mistake direct ADCC for another form of CTL activity. These two highly potent reactivities operate independently and are subject to different control mechanisms, both positive and negative, anti-viral ADCC has too long been regarded as a strictly in vitro phenomenon with no in vivo counterpart. Our studies demonstrating direct forms of ADCC in infected patients will hopefully have some impact in forcing a careful re-evaluation of this extremely important issue.

Authors
Weinhold, KJ; Tyler, DS; Lyerly, HK
MLA Citation
Weinhold, KJ, Tyler, DS, and Lyerly, HK. "Measurement of direct and indirect forms of anti-HIV-1 ADCC: implications for other retroviral disease." Dev Biol Stand 72 (1990): 343-348.
PMID
2282991
Source
pubmed
Published In
Developments in Biologicals
Volume
72
Publish Date
1990
Start Page
343
End Page
348

Survey: Invited commentary (I)

Authors
Lyerly, HK
MLA Citation
Lyerly, HK. "Survey: Invited commentary (I)." Archives of Surgery 125.6 (1990): 768--.
Source
scival
Published In
Archives of Surgery
Volume
125
Issue
6
Publish Date
1990
Start Page
768-

Commercially available surgical gowns do not prevent penetration by HIV-1

Authors
Shadduck, PP; Tyler, DS; Lyerly, HK; Sebastian, MW; Farnitano, C; Fitzpatrick, KT; Langlois, AJ; Moylan, JA
MLA Citation
Shadduck, PP, Tyler, DS, Lyerly, HK, Sebastian, MW, Farnitano, C, Fitzpatrick, KT, Langlois, AJ, and Moylan, JA. "Commercially available surgical gowns do not prevent penetration by HIV-1." Surgical Forum 41 (1990): 77-80.
Source
scival
Published In
Surgical Forum
Volume
41
Publish Date
1990
Start Page
77
End Page
80

Anti-HIV-1 ADCC.

Authors
Tyler, DS; Lyerly, HK; Weinhold, KJ
MLA Citation
Tyler, DS, Lyerly, HK, and Weinhold, KJ. "Anti-HIV-1 ADCC." AIDS Res Hum Retroviruses 5.6 (December 1989): 557-563. (Review)
PMID
2692657
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
5
Issue
6
Publish Date
1989
Start Page
557
End Page
563
DOI
10.1089/aid.1989.5.557

Barrier protection against the human immunodeficiency virus.

Authors
Tyler, DS; Lyerly, HK; Nastala, CL; Shadduck, PP; Fitzpatrick, KT; Langlois, AJ; Moylan, JA
MLA Citation
Tyler, DS, Lyerly, HK, Nastala, CL, Shadduck, PP, Fitzpatrick, KT, Langlois, AJ, and Moylan, JA. "Barrier protection against the human immunodeficiency virus." Curr Surg 46.4 (July 1989): 301-304.
PMID
2766799
Source
pubmed
Published In
Current Surgery
Volume
46
Issue
4
Publish Date
1989
Start Page
301
End Page
304

HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection.

The magnitude of immunologic defects observed in HIV-1-infected individuals before the development of overt AIDS is disproportionately high in comparison to the levels of infectious virus in these patients--suggesting that factors other than direct virus-induced cytopathology may be involved. With this in mind, we investigated the immunologic consequences of the interaction between purified HIV-1 gp120 and the CD4 molecules expressed by uncommitted as well as Ag-specific lymphocytes. HIV-1 gp120 exhibited a dose-dependent immunosuppressive effect on: 1) Ag-driven proliferation of cloned CD4+ lymphocytes, 2) OKT3-driven proliferation of cloned CD4+ lymphocytes, and 3) cytolytic activity of CD4+, EBV-specific CTL. Thus, HIV-1 gp120 can, in a manner similar to OKT4A antibodies, suppress T cell activation and the expression of cytolytic activities through its interaction with CD4. Additionally, activated CD4+ lymphoblasts can be rendered susceptible to immune cytolysis by virtue of their binding of purified gp120. This "targeting" of activated lymphoblasts can occur with levels of gp120 far below that which is needed to saturate all OKT4A-defined CD4 epitopes. Adsorbed gp120 could be demonstrated on the surface of these cells for up to 12 h, a sufficient time for interaction with host cytolytic elements. The data from these in vitro modeling experiments highlight one of many potential mechanisms of HIV-1 induced immunosuppression and lymphocyte destruction that can occur in the absence of infectious virus and that is based on the unique interaction between HIV-1 gp120 and its cellular receptor, CD4.

Authors
Weinhold, KJ; Lyerly, HK; Stanley, SD; Austin, AA; Matthews, TJ; Bolognesi, DP
MLA Citation
Weinhold, KJ, Lyerly, HK, Stanley, SD, Austin, AA, Matthews, TJ, and Bolognesi, DP. "HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection." J Immunol 142.9 (May 1, 1989): 3091-3097.
PMID
2468713
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
142
Issue
9
Publish Date
1989
Start Page
3091
End Page
3097

Utility of Doppler color flow imaging for identification of femoral arterial complications of cardiac catheterization.

Doppler color flow and two-dimensional ultrasonographic images of the femoral region were obtained in 25 patients referred for suspected vascular complications of cardiac catheterization. Five patients had normal findings, while 23 abnormalities were noted in 20 patients, including seven femoral arteriovenous fistulae, 12 femoral pseudoaneurysms, and two patients with both femoral arteriovenous fistulas and pseudoaneurysms. Operation confirmed the abnormalities diagnosed by color flow examination in 15 of 20 patients. Three patients refused operation and one was not felt to be a surgical candidate due to high anesthetic risk. One patient died preoperatively and postmortem examination confirmed the color flow diagnosis. Etiologies of the arterial complications included percutaneous aortic valvuloplasty (6), coronary angioplasty (4), and arterial or both arterial and venous catheterization (10). Doppler color flow imaging is a reliable technique for identification of vascular complications following catheterization procedures.

Authors
Sheikh, KH; Adams, DB; McCann, R; Lyerly, HK; Sabiston, DC; Kisslo, J
MLA Citation
Sheikh, KH, Adams, DB, McCann, R, Lyerly, HK, Sabiston, DC, and Kisslo, J. "Utility of Doppler color flow imaging for identification of femoral arterial complications of cardiac catheterization." Am Heart J 117.3 (March 1989): 623-628.
PMID
2521974
Source
pubmed
Published In
American Heart Journal
Volume
117
Issue
3
Publish Date
1989
Start Page
623
End Page
628

GP120 specific cellular cytotoxicity in HIV-1 seropositive individuals. Evidence for circulating CD16+ effector cells armed in vivo with cytophilic antibody.

Fresh circulating PBMC from HIV-1 seropositive individuals have been found to mediate specific, non-MHC restricted lysis of targets expressing the major envelope glycoprotein of HIV-1, gp120, in 6-h 51Cr release assays. This gp120 specific cell-mediated cytotoxicity (CMC) is broadly reactive against target cells infected with a wide range of viral isolates, is IL-2 augmentable, and is mediated by a CD16+, Leu-7+, CD15-, CD3- population of NK/K cells. The presence of FcR (CD16) on these cells suggested that the lytic specificity for gp120 might be directed by cytophilic antibody bound to the cell surface. Affinity purified F(ab')2 antibody fragments specific for the Fc and F(ab')2 portions of human IgG were used in attempts to block gp120 specific lysis. A 1/50 dilution of these antibodies inhibited gp120 specific cytolytic activity by more than 90% while exhibiting a minimal effect on NK/K cell lysis of K562 targets. The blocking activity of these fragments demonstrates the direct involvement of cytophilic antibody in CMC. In attempts to isolate this cytophilic anti-HIV-1 antibody, short 56 degrees C incubations were used to dissociate antibodies from the surface of PBMC of seropositive individuals. The supernatants generated in this manner exhibited specific gp120 activity in antibody-dependent cellular cytotoxicity assays. The ability of Staphylococcal protein A to remove this activity confirms the presence of cytophilic antibody on freshly isolated PBMC. Selective enrichment of specific cell subpopulations revealed the origin of the cytophilic antibody to be CD16+ NK/K cells and not B cells, T cells, or monocytes/macrophages. These studies show that the gp120-specific CMC seen in HIV-1 seropositive individuals is directed by cytophilic antibody bound to circulating CD16+ NK/K cells and represents a form of direct antibody-dependent cellular cytotoxicity which may provide a primary cytotoxic host defense.

Authors
Tyler, DS; Nastala, CL; Stanley, SD; Matthews, TJ; Lyerly, HK; Bolognesi, DP; Weinhold, KJ
MLA Citation
Tyler, DS, Nastala, CL, Stanley, SD, Matthews, TJ, Lyerly, HK, Bolognesi, DP, and Weinhold, KJ. "GP120 specific cellular cytotoxicity in HIV-1 seropositive individuals. Evidence for circulating CD16+ effector cells armed in vivo with cytophilic antibody." J Immunol 142.4 (February 15, 1989): 1177-1182.
PMID
2536767
Source
pubmed
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
142
Issue
4
Publish Date
1989
Start Page
1177
End Page
1182

Cellular immune response to viral peptides in patients exposed to HIV.

In efforts to identify B cell and T cell epitopes of HIV-1 structural components, serum as well as lymphocytes from HIV-1-seropositive individuals were reacted with several recombinant and native peptides representing defined viral gag and env determinants. Several areas of discordance between humoral and cellular reactivity were identified. Specifically, the principal neutralizing site within HIV-1, the major envelope glycoprotein gp120, failed to elicit detectable cellular reactivities. The carboxyl portion of gp120 and the transmembrane gp41 region were uniformly recognized by patient antibodies but did not produce significant lymphocyte blastogenesis. However, the amino half of gp120 elicited cellular responses in a majority of the immunocompetent individuals tested, despite its extremely low reactivity with patient sera. Last, the major HIV-1 structure component p24 was found to be the most consistent T cell activation antigen among the panel tested.

Authors
Ahearne, PM; Matthews, TJ; Lyerly, HK; White, GC; Bolognesi, DP; Weinhold, KJ
MLA Citation
Ahearne, PM, Matthews, TJ, Lyerly, HK, White, GC, Bolognesi, DP, and Weinhold, KJ. "Cellular immune response to viral peptides in patients exposed to HIV." AIDS Res Hum Retroviruses 4.4 (August 1988): 259-267.
PMID
2462895
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
4
Issue
4
Publish Date
1988
Start Page
259
End Page
267
DOI
10.1089/aid.1988.4.259

Characteristics of a neutralizing monoclonal antibody to the HIV envelope glycoprotein.

We have studied the biologic and physical properties of a monoclonal antibody that binds to gp120, the exterior envelope glycoprotein of the human immunodeficiency virus (HIV) strain HTLV-IIIB. Designated 9284, the antibody possesses viral neutralizing activity and inhibits syncytium formation by infected cells. The antibody recognized a region of the polypeptide backbone previously described as an important neutralizing epitope. This region lies 307-330 residues from amino terminus of the glycoprotein. We have compared the biologic and physical properties of this antibody to those of the recently described 0.5 beta monoclonal antibody to gp120. The 0.5 beta antibody was biologically more potent and bound an epitope slightly downstream to that of the 9284 antibody. The antibodies did not differ significantly in their affinity for gp120. In competition studies, the 0.5 beta antibody was displaced by the 9284 antibody, but the binding of the latter was unaffected by 0.5 beta.

Authors
Skinner, MA; Ting, R; Langlois, AJ; Weinhold, KJ; Lyerly, HK; Javaherian, K; Matthews, TJ
MLA Citation
Skinner, MA, Ting, R, Langlois, AJ, Weinhold, KJ, Lyerly, HK, Javaherian, K, and Matthews, TJ. "Characteristics of a neutralizing monoclonal antibody to the HIV envelope glycoprotein." AIDS Res Hum Retroviruses 4.3 (June 1988): 187-197.
PMID
2456088
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
4
Issue
3
Publish Date
1988
Start Page
187
End Page
197
DOI
10.1089/aid.1988.4.187

Cellular anti-GP120 cytolytic reactivities in HIV-1 seropositive individuals.

Forty-one patients seropositive for human immunodeficiency virus type 1 (HIV-1) were assessed for cell-mediated cytotoxicity (CMC) against autologous target cells bearing the major envelope glycoprotein of HIV-1, gp120. Effector lymphocytes from over 85% of seropositive patients showed CMC specific for gp120-coated targets, whereas seronegative individuals had no detectable CMC. As a group, symptomless individuals had the highest levels of CMC; patients with AIDS-related complex and AIDS showed progressively diminished reactivity. The gp120-specific CMC was mediated by a population of non-T-cell effectors phenotypically resembling NK/K cells. Cytolysis was not restricted by major histocompatibility complex determinants, as shown by killing of heterologous gp120-adsorbed targets and of HIV-1-infected cell-lines. Gp120-specific CMC was highly augmented in the presence of interleukin 2, so it may be possible to develop therapeutic strategies aimed at destruction of virus-producing cell reservoirs in infected individuals through stimulation of HIV-specific host CMC.

Authors
Weinhold, KJ; Lyerly, HK; Matthews, TJ; Tyler, DS; Ahearne, PM; Stine, KC; Langlois, AJ; Durack, DT; Bolognesi, DP
MLA Citation
Weinhold, KJ, Lyerly, HK, Matthews, TJ, Tyler, DS, Ahearne, PM, Stine, KC, Langlois, AJ, Durack, DT, and Bolognesi, DP. "Cellular anti-GP120 cytolytic reactivities in HIV-1 seropositive individuals." Lancet 1.8591 (April 23, 1988): 902-905.
PMID
2895830
Source
pubmed
Published In
The Lancet
Volume
1
Issue
8591
Publish Date
1988
Start Page
902
End Page
905

Anti-HIV-1 immune cytolysis is independent of viral envelope glycosylation

Authors
Lyerly, HK; Skinner, MA; Tyler, DS; Nastala, CL; Matthews, TJ; Bolognesi, DP; Weinhold, KJ
MLA Citation
Lyerly, HK, Skinner, MA, Tyler, DS, Nastala, CL, Matthews, TJ, Bolognesi, DP, and Weinhold, KJ. "Anti-HIV-1 immune cytolysis is independent of viral envelope glycosylation." Surgical Forum 39 (1988): 420-422.
Source
scival
Published In
Surgical Forum
Volume
39
Publish Date
1988
Start Page
420
End Page
422

Direct antibody-dependent cellular cytotoxicity: Evidence of circulating antibody-armed cytotoxic CD16+ NK/K cells in patients infected with HIV-1

Authors
Tyler, DS; Nastala, CL; Lyerly, HK; Matthews, TJ; Bolognesi, DP; Weinhold, KJ
MLA Citation
Tyler, DS, Nastala, CL, Lyerly, HK, Matthews, TJ, Bolognesi, DP, and Weinhold, KJ. "Direct antibody-dependent cellular cytotoxicity: Evidence of circulating antibody-armed cytotoxic CD16+ NK/K cells in patients infected with HIV-1." Surgical Forum 39 (1988): 418-420.
Source
scival
Published In
Surgical Forum
Volume
39
Publish Date
1988
Start Page
418
End Page
420

Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells.

The human immunodeficiency virus envelope gene was expressed in insect cells by using a Baculovirus expression vector. The protein has an apparent molecular mass of 160 kDa, appears on the surface of infected insect cells, and does not appear to be cleaved to glycoproteins gp120 and gp41. Goats immunized with the 160-kDa protein have high titers of antibody that neutralizes virus infection as measured by viral gene expression or cell cytolysis. In addition, immune sera can block fusion of human immunodeficiency virus-infected cells in culture. Both neutralization and fusion-blocking activities are bound to and eluted from immobilized gp120.

Authors
Rusche, JR; Lynn, DL; Robert-Guroff, M; Langlois, AJ; Lyerly, HK; Carson, H; Krohn, K; Ranki, A; Gallo, RC; Bolognesi, DP
MLA Citation
Rusche, JR, Lynn, DL, Robert-Guroff, M, Langlois, AJ, Lyerly, HK, Carson, H, Krohn, K, Ranki, A, Gallo, RC, and Bolognesi, DP. "Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells." Proc Natl Acad Sci U S A 84.19 (October 1987): 6924-6928.
PMID
3477816
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
84
Issue
19
Publish Date
1987
Start Page
6924
End Page
6928

Interaction between the human T-cell lymphotropic virus type IIIB envelope glycoprotein gp120 and the surface antigen CD4: role of carbohydrate in binding and cell fusion.

Interactions between retroviruses associated with acquired immunodeficiency syndrome and their receptors on lymphocytes represent the initial steps in the process of infection and are also involved in multinucleated giant cell formation, which is one form of virus-mediated cytopathology. The exterior envelope glycoprotein of the retrovirus has been identified as gp120, and we demonstrate here that purified gp120 binds directly to cells expressing the CD4 (T4) surface antigen at a site spatially related to that recognized by the OKT4A monoclonal antibody. The gp120 was also able to temporarily interfere with viral infection and to block the process of multinucleated giant cell formation. However, if the carbohydrate chains were removed from gp120 by enzymatic treatment, CD4 binding and blockade of cell fusion was reduced by about a factor of 50. The significance of these results in relation to preventive and interventive approaches for acquired immunodeficiency syndrome is discussed.

Authors
Matthews, TJ; Weinhold, KJ; Lyerly, HK; Langlois, AJ; Wigzell, H; Bolognesi, DP
MLA Citation
Matthews, TJ, Weinhold, KJ, Lyerly, HK, Langlois, AJ, Wigzell, H, and Bolognesi, DP. "Interaction between the human T-cell lymphotropic virus type IIIB envelope glycoprotein gp120 and the surface antigen CD4: role of carbohydrate in binding and cell fusion." Proc Natl Acad Sci U S A 84.15 (August 1987): 5424-5428.
PMID
3037551
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
84
Issue
15
Publish Date
1987
Start Page
5424
End Page
5428

Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack.

The lymphocyte differentiation antigen CD4 serves as a receptor for human retroviruses associated with acquired immunodeficiency syndrome (AIDS) through its interaction with the major envelope virion glycoprotein, gp120, which is also expressed on the surface of infected cells. In these experiments, purified gp120 was shown to bind to normal human T-lymphocyte populations. The gp120-CD4 complex served as a target antigen for antibody-dependent complement-mediated cytolysis by a goat serum raised against native gp120. However, patient sera that bound to gp120-adsorbed cells failed to direct their destruction in the presence of complement. In contrast, these sera were potent mediators of antibody-dependent cellular cytotoxicity. These studies demonstrate that gp120 situated on the cell surface can serve as an effective target for immune destruction by patient antibodies and effector lymphocytes. The possible contribution of this type of immunity to control of disease progression, on the one hand, and to lymphocyte destruction and immunopathology observed in AIDS, on the other, is discussed.

Authors
Lyerly, HK; Matthews, TJ; Langlois, AJ; Bolognesi, DP; Weinhold, KJ
MLA Citation
Lyerly, HK, Matthews, TJ, Langlois, AJ, Bolognesi, DP, and Weinhold, KJ. "Human T-cell lymphotropic virus IIIB glycoprotein (gp120) bound to CD4 determinants on normal lymphocytes and expressed by infected cells serves as target for immune attack." Proc Natl Acad Sci U S A 84.13 (July 1987): 4601-4605.
PMID
3037522
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
84
Issue
13
Publish Date
1987
Start Page
4601
End Page
4605

Prospects for development of a vaccine against HTLV-III-related disorders.

Authors
Matthews, TJ; Lyerly, HK; Weinhold, KJ; Langlois, AJ; Rusche, J; Putney, SD; Gallo, RC; Bolognesi, DP
MLA Citation
Matthews, TJ, Lyerly, HK, Weinhold, KJ, Langlois, AJ, Rusche, J, Putney, SD, Gallo, RC, and Bolognesi, DP. "Prospects for development of a vaccine against HTLV-III-related disorders." AIDS Res Hum Retroviruses 3 Suppl 1 (1987): 197-206. (Review)
PMID
2825738
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
3 Suppl 1
Publish Date
1987
Start Page
197
End Page
206
DOI
10.1089/aid.1987.3.197

Transmission of HIV by antigen presenting cells during T-cell activation: prevention by 3'-azido-3'-deoxythymidine.

Tetanus toxoid (TT) reactive CD4+ cells were infected with HTLV-IIIB and exposed to TT at various times throughout a 7-day interval. Acute infection per se failed to produce overt cytopathology. However, exposure of infected cells to TT resulted in a rapid loss of cell viability, an increase in viral p24 expression, and a decline in T-cell blastogenesis. To determine whether HIV infection of antigen presenting cells (APC) could impact on T-cell activation, virus infected APC were utilized to present TT to responsive CD4+ cells. Use of infected APC produced effects similar to antigen stimulation of infected T-cells. These results suggest that the conditions of antigen presentation during T-cell activation may provide an excellent opportunity for virus transmission which may produce maximal immune dysfunction. However, preincubating antigen specific T-cells with the virostatic agent 3'-azido-3'-deoxythymidine (AZT) could prevent most of these effects.

Authors
Lyerly, HK; Cohen, OJ; Weinhold, KJ
MLA Citation
Lyerly, HK, Cohen, OJ, and Weinhold, KJ. "Transmission of HIV by antigen presenting cells during T-cell activation: prevention by 3'-azido-3'-deoxythymidine." AIDS Res Hum Retroviruses 3.1 (1987): 87-94.
PMID
3497654
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
3
Issue
1
Publish Date
1987
Start Page
87
End Page
94
DOI
10.1089/aid.1987.3.87

Anti-GP 120 antibodies from HIV seropositive individuals mediate broadly reactive anti-HIV ADCC.

Cytophilic antibodies which mediate antibody dependent cellular cytotoxicity (ADCC) against envelope antigens of human immunodeficiency virus (HIV) can be found in seropositive individuals. In these experiments, sera from a wide spectrum of HIV infected patients ranging from asymptomatic to overt acquired immunodeficiency syndrome (AIDS) were shown to contain high titers of antibodies that mediate ADCC. Not only did patient antibodies bind to surface expressed viral antigens and mediate ADCC against cells chronically infected with human T-lymphotropic virus type IIIB (HTLV-IIIB), but also against cells infected with the divergent HTLV-IIIRF2 and HTLV-IIIMN viral isolates. Similar results were obtained with target cells bearing purified GP 120 from HTLV-IIIB and HTLV-IIIRF2, indicating that a major portion of the activity was mediated by anti-GP 120 antibodies. Consistent with this was the ability to absorb most of the group-specific ADCC activity from the serum of an HIV infected individual using affinity columns bearing purified HTLV-IIIB GP 120. The finding that human antibodies reactive against the HIV envelope glycoprotein mediate ADCC against cells chronically infected with divergent strains of HIV will have important implications in designing rational approaches to passive and active immunotherapy.

Authors
Lyerly, HK; Reed, DL; Matthews, TJ; Langlois, AJ; Ahearne, PA; Petteway, SR; Weinhold, KJ
MLA Citation
Lyerly, HK, Reed, DL, Matthews, TJ, Langlois, AJ, Ahearne, PA, Petteway, SR, and Weinhold, KJ. "Anti-GP 120 antibodies from HIV seropositive individuals mediate broadly reactive anti-HIV ADCC." AIDS Res Hum Retroviruses 3.4 (1987): 409-422.
PMID
2833917
Source
pubmed
Published In
AIDS Research and Human Retroviruses
Volume
3
Issue
4
Publish Date
1987
Start Page
409
End Page
422
DOI
10.1089/aid.1987.3.409

Prospects for development of a vaccine against HIV-related disorders

Authors
Matthews, TJ; Lyerly, HK; Weinhold, KJ; Langlois, AJ; Putney, SD; Bolognesi, DP
MLA Citation
Matthews, TJ, Lyerly, HK, Weinhold, KJ, Langlois, AJ, Putney, SD, and Bolognesi, DP. "Prospects for development of a vaccine against HIV-related disorders." Clinical Immunology Newsletter 8.4 (1987): 49-52.
Source
scival
Published In
Clinical Immunology Newsletter
Volume
8
Issue
4
Publish Date
1987
Start Page
49
End Page
52

Augmentation of anti-HIV ADCC with interleukin-2

Authors
Lyerly, HK; Matthews, TJ; Aherne, PM; Langlois, AJ; Bolognesi, DP; Weinhold, KJ
MLA Citation
Lyerly, HK, Matthews, TJ, Aherne, PM, Langlois, AJ, Bolognesi, DP, and Weinhold, KJ. "Augmentation of anti-HIV ADCC with interleukin-2." Surgical Forum 38 (1987): 425-428.
Source
scival
Published In
Surgical Forum
Volume
38
Publish Date
1987
Start Page
425
End Page
428

TYPE SPECIFIC BINDING OF SURFACE EXPRESSED GP120 BY ANTI-GP120 SERUM

Authors
LYERLY, HK; WEINHOLD, KJ; MATTHEWS, TJ; PUTNEY, S; RUSCHE, J; LANGLOIS, AJ; BOLOGNESI, DP
MLA Citation
LYERLY, HK, WEINHOLD, KJ, MATTHEWS, TJ, PUTNEY, S, RUSCHE, J, LANGLOIS, AJ, and BOLOGNESI, DP. "TYPE SPECIFIC BINDING OF SURFACE EXPRESSED GP120 BY ANTI-GP120 SERUM." 1987.
Source
wos-lite
Published In
Journal of Cellular Biochemistry
Publish Date
1987
Start Page
73
End Page
73

Management of primary sarcomas of the pulmonary artery and reperfusion intrabronchial hemorrhage.

Authors
Lyerly, HK; Reves, JG; Sabiston, DC
MLA Citation
Lyerly, HK, Reves, JG, and Sabiston, DC. "Management of primary sarcomas of the pulmonary artery and reperfusion intrabronchial hemorrhage." Surg Gynecol Obstet 163.3 (September 1986): 291-301. (Review)
PMID
3529465
Source
pubmed
Published In
Surgery Gynecology and Obstetrics
Volume
163
Issue
3
Publish Date
1986
Start Page
291
End Page
301

Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex.

In a 6-week clinical trial 4 dose regimens of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue with potent anti-viral activity against HTLV-III in vitro, were examined in 19 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). AZT was given intravenously for 2 weeks, then orally for 4 weeks at twice the intravenous dose. AZT was well absorbed from the gut and crossed the blood-brain barrier. Therapeutic levels were maintained with 5 mg given intravenously or 10 mg given orally every 4 h. Treatment was not limited by side-effects, the commonest of which were headaches and depression of white-cell counts. 15 of the 19 patients had increases in their numbers of circulating helper-inducer T lymphocytes (p less than 0.001) during therapy, 6 who were anergic at entry showed positive delayed type hypersensitivity skin test reactions during treatment, 2 had clearance of chronic fungal nailbed infections without specific anti-fungal therapy, 6 had other evidence of clinical improvement, and the group as a whole had a weight gain of 2.2 kg. Also, with the highest dose regimen cultures of peripheral blood mononuclear cells for HTLV III became negative.

Authors
Yarchoan, R; Klecker, RW; Weinhold, KJ; Markham, PD; Lyerly, HK; Durack, DT; Gelmann, E; Lehrman, SN; Blum, RM; Barry, DW
MLA Citation
Yarchoan, R, Klecker, RW, Weinhold, KJ, Markham, PD, Lyerly, HK, Durack, DT, Gelmann, E, Lehrman, SN, Blum, RM, and Barry, DW. "Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex." Lancet 1.8481 (March 15, 1986): 575-580.
PMID
2869302
Source
pubmed
Published In
The Lancet
Volume
1
Issue
8481
Publish Date
1986
Start Page
575
End Page
580

Radiographic findings in pulmonary hypertension from unresolved embolism.

Pulmonary artery hypertension with chronic pulmonary embolism is an uncommon entity that is potentially treatable with pulmonary embolectomy. Although the classic radiographic features have been described, several recent investigators report a significant percentage of these patients with normal chest radiographs. In a series of 22 patients, no normal radiographs were seen. Findings included cardiomegaly (86.4%) with right-sided enlargement (68.4%), right descending pulmonary artery enlargement (54.5%), azygos vein enlargement (27.3%), mosaic oligemia (68.2%), chronic volume loss (27.3%), atelectasis and/or effusion (22.7%), and pleural thickening (13.6%). Good correlation with specific areas of diminished vascularity was seen on chest radiographs compared with pulmonary angiograms.

Authors
Woodruff, WW; Hoeck, BE; Chitwood, WR; Lyerly, HK; Sabiston, DC; Chen, JT
MLA Citation
Woodruff, WW, Hoeck, BE, Chitwood, WR, Lyerly, HK, Sabiston, DC, and Chen, JT. "Radiographic findings in pulmonary hypertension from unresolved embolism." AJR Am J Roentgenol 144.4 (April 1985): 681-686.
PMID
3872021
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
144
Issue
4
Publish Date
1985
Start Page
681
End Page
686
DOI
10.2214/ajr.144.4.681

Surgical management of chronic pulmonary embolism.

Recurrent pulmonary emboli ultimately may produce respiratory insufficiency, severe hypoxemia, and progressive pulmonary hypertension. In many patients this syndrome is silent in its initial phases, and when thrombophlebitis is present it is often unresponsive to anticoagulant therapy. Unless pulmonary embolectomy is undertaken, most of these patients characteristically succumb with severe respiratory insufficiency. Twenty-five patients with this syndrome have been evaluated at the Duke University Medical Center, and 14 were selected for elective pulmonary embolectomy for relief of severe and incapacitating pulmonary insufficiency. In each patient preoperative pulmonary scans and arteriography demonstrated a high degree of vascular occlusion. The obstructing lesions affected both lungs in the majority of patients. Bronchial arteriography was found to be a very valuable method for demonstrating patency of the pulmonary arteries distal to occluding lesions by retrograde filling through collateral vessels joining the bronchial and pulmonary circulations. Preoperatively radionuclide angiocardiography revealed severe right ventricular dysfunction with significantly depressed ejection fractions at rest and during exercise. Retrograde pulmonary arterial flow as shown by selective bronchial arteriography was excellent in ten patients, fair in three, and absent in one. Long term follow-up indicated a clear relationship between the magnitude of arterial backflow at the time of embolectomy and the degree of clinical improvement. There were two perioperative deaths, one from massive reperfusion pulmonary hemorrhage and another from intractable right ventricular failure. Eleven patients with this syndrome were unsuitable candidates for embolectomy and of these, nine had severe distal emboli diffusely spread in the small pulmonary arteries and not amenable to direct removal. One patient had severe right ventricular failure with extreme pulmonary hypertension (145/45 mmHg) and another was massively obese with severe congestive heart failure and expired in the hospital a week later. In this group of 11 patients, three succumbed and most of the others are currently totally debilitated at rest (NYHA Class IV). Long-term follow-up of the surgically managed patients (1 to 15 years) shows that ten patients improved from NYHA functional Class IV to either I or II, another patient from Class III to Class I, and a final patient was only minimally improved.(ABSTRACT TRUNCATED AT 400 WORDS)

Authors
Chitwood, WR; Lyerly, HK; Sabiston, DC
MLA Citation
Chitwood, WR, Lyerly, HK, and Sabiston, DC. "Surgical management of chronic pulmonary embolism." Ann Surg 201.1 (January 1985): 11-26.
PMID
3966827
Source
pubmed
Published In
Annals of Surgery
Volume
201
Issue
1
Publish Date
1985
Start Page
11
End Page
26

Voluntary control of the human vestibulo-ocular reflex

The ability of normal subjects to increase their vestibulo-ocular reflex (VOR) gain with an imagined stationary frame of reference was dependent on their strategy and the test conditions. With large amplitude sinusoidal rotation (>50 degrees) subjects could not increase their VOR gain regardless of the strategy used. With small amplitude excursions (<50 degrees) they could significantly increase their VOR gain if they used a 'single stripe' strategy. Accompanying this increase in VOR gain was an increase in the phase lead of VOR slow phase velocity relative to head velocity. Apparently the signal used to augment the VOR gain with an imagined stationary surround had phase characteristics similar to those of primary vestibular afferent neurons.

Authors
Baloh, RW; Lyerly, K; Yee, RD; Honrubia, V
MLA Citation
Baloh, RW, Lyerly, K, Yee, RD, and Honrubia, V. "Voluntary control of the human vestibulo-ocular reflex." Acta Oto-Laryngologica 97.1-2 (1984): 1-6.
PMID
6606285
Source
scival
Published In
Acta Oto-Laryngologica
Volume
97
Issue
1-2
Publish Date
1984
Start Page
1
End Page
6
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