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Sampson, John Howard

Overview:

Current research activities involve the immunotherapeutic targeting of a tumor-specific mutation in the epidermal growth factor receptor. Approaches used to target this tumor-specific epitope include unarmed and radiolabeled antibody therapy and cell mediated approaches using peptide vaccines and dendritic cells. Another area of interest involves drug delivery to brain tumors. Translational and clinical work is carried out in this area to formulate the relationship between various direct intratumoral infusion parameters and drug distribution within brain tumors and normal brain.

The Duke Brain Tumor Immunotherapy Program (BTIP) has an emphasis on translational research in Neuro-Oncology. There are two main areas of study. The first is novel mechanisms of delivery of large molecular weight molecules, such as monoclonal antibodies, throughout brain intersitial space using novel intracerebral infusion techniques developed by this laboratory. Studies exploring this technology are undertaken in both small and large laboratory animals and patients with brain tumors.

The other focus of the BTIP is translational immunotherapy. In this line of work, dendritic cell vaccination strategies and adoptive T-cell strategies have been developed to target novel and well-characterized tumor-specific antigens in patients with brain tumors. The BTIP integrates well with and works closely with the Preston Robert Tisch Brain Tumor Center at Duke. The BTIP is well funded and currently holds seven NIH grants, including a SPORE in Brain Cancer grant. There are a large number of investigators at various levels so that students will get exposure to various levels of research and mentorship.

Positions:

Robert H., M.D. and Gloria Wilkins Professor of Neurosurgery, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Professor of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Professor of Immunology

Immunology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Professor of Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chair, Department of Neurosurgery

Neurosurgery
School of Medicine

Education:

M.D. 1990

M.D. — University of Manitoba (Canada)

Ph.D. 1996

Ph.D. — Duke University

M.H.S. 2007

M.H.S. — Duke University School of Medicine

M.B.A. 2011

M.B.A. — Duke University

Investigator In Cerebral Hydrodynamics Lab, Neurosurgery

University of Manitoba (Canada)

Intern, Surgery

Duke University

Resident In Neurosurgery, Surgery

Duke University

Ph.D. Program In Pathology, Surgery

Duke University

News:

Grants:

Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
August 01, 2015
End Date
July 31, 2022

CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 2016
End Date
November 30, 2021

Translational Research in Surgical Oncology

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

Role of GLUD2 as a metabolic driver of gliomas with IDH1 mutations

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
September 30, 2016
End Date
June 30, 2021

Human EGFRvIII-specific BiTE for the treatment of Glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2020

Duke SPORE in Brain Cancer

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 24, 2014
End Date
August 31, 2019

NINDS Research Education Programs for Residents and Fellows in Neurosurgery

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2009
End Date
June 30, 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

Quantitative Staging and Therapeutic Response in IDH-1 Mutated Glioblastomas

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 01, 2017
End Date
February 28, 2019

Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 2015
End Date
February 28, 2019

Brain Tumor Targeting Using Tumor-Specific Neuroimmunology

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 15, 2014
End Date
May 31, 2018

EGFRvIII-targeted Bispecific T cell Engagers for brain tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2013
End Date
May 31, 2018

Targeting Translation Control in Malignant Glioma

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
January 17, 2007
End Date
May 31, 2018

Brain tumors with regulatory T-cells treated with EGFRvIII-specific T-cells

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 05, 2013
End Date
March 31, 2018

PBTF Institute Grant

Administered By
Neurosurgery
AwardedBy
Pediatric Brain Tumor Foundation
Role
Principal Investigator
Start Date
January 01, 2015
End Date
December 31, 2017

A clinically-relevant anti-CD27 agonist antibody as a vaccine adjuvant for brain tumor immunotherapy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2016
End Date
July 31, 2017

Enhancing dendritic cell migration to drive potent anti-tumor immune responses

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2013
End Date
June 30, 2017

Medical Scientist Training Program

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1997
End Date
June 30, 2017

Use of YH24931 in combination with antigen-specific DC vaccines for antitumor efficacy

Administered By
Neurosurgery
AwardedBy
Yuhan Corporation
Role
Significant Contributor
Start Date
December 20, 2016
End Date
June 19, 2017

Pediatric Brain Tumor Consortium

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Collaborator
Start Date
April 01, 2014
End Date
March 31, 2017

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

HFTL event

Administered By
Neurosurgery
AwardedBy
BrainLAB, Inc.
Role
Principal Investigator
Start Date
May 09, 2016
End Date
May 19, 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

Clinical Oncology Research Career Development Program

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

Development of peptide vaccine for diffuse intrinsic pontine glioma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
The Cure Starts Now
Role
Co Investigator
Start Date
November 01, 2013
End Date
October 31, 2014

Convection Enhanced Delivery of Chemokines can increase T-Cell Chemotaxis to Brain Tumors in an Adoptive T cell Model

Administered By
Neurosurgery
AwardedBy
American Brain Tumor Association
Role
Principal Investigator
Start Date
June 01, 2014
End Date
August 31, 2014

Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 2013
End Date
April 30, 2014

Modulation of the blood-tumor barrier through targeted suppression of claudin 5

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 16, 2011
End Date
August 02, 2013

RNA-based Immunotherapy Targeting Antigens Unique to Brain Tumor Stem Cells

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2008
End Date
May 31, 2013

Enterovirus Vectors with Respiratory Tropism for Cancer Immunotherapy

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 15, 2009
End Date
August 31, 2012

Neuroimmunology of Vaccines in Adoptive T-cell Therapy for Brain Tumor

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2010
End Date
June 30, 2012

Pre-clinical Translation of Regulatory T-cell Inhibition in Brain Tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 2010
End Date
June 30, 2012

Gene Targeted Therapy of Brain Tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2009
End Date
February 29, 2012

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Effect on IL-2R Antibody on Regulatory T-cells in Patients with Malignant Gliomas

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 04, 2008
End Date
December 31, 2009

Dendritic Cell Immunotherapy of Malignant Gliomas

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2002
End Date
August 31, 2008

Intracerebral Infusion of Radiolabeled Specific Antibody

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2002
End Date
August 31, 2008

Regional AGT Depletion of CNS and Leptomeningeal Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 01, 2002
End Date
January 31, 2006

GCRC CAP

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2000
End Date
August 31, 2005
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Publications:

The Safety of available immunotherapy for the treatment of glioblastoma.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Current standard of care involves maximal surgical resection combined with adjuvant chemoradiation. Growing support exists for a role of immunotherapy in treating these tumors with the goal of targeted cytotoxicity. Here we review data on the safety for current immunotherapies being tested in GBM. Areas covered: Safety data from published clinical trials, including ongoing clinical trials were reviewed. Immunotherapeutic classes currently under investigation in GBM include various vaccination strategies, adoptive T cell immunotherapy, immune checkpoint blockade, monoclonal antibodies, and cytokine therapies. Trials include children, adolescents, and adults with either primary or recurrent GBM. Expert opinion: Based on the reviewed clinical trials, the current immunotherapies targeting GBM are safe and well-tolerated with minimal toxicities which should be noted. However, the gains in patient survival have been modest. A safe and well-tolerated combinatory immunotherapeutic approach may be essential for optimal efficacy towards GBM.

Authors
Farber, SH; Elsamadicy, AA; Atik, AF; Suryadevara, CM; Chongsathidkiet, P; Fecci, PE; Sampson, JH
MLA Citation
Farber, SH, Elsamadicy, AA, Atik, AF, Suryadevara, CM, Chongsathidkiet, P, Fecci, PE, and Sampson, JH. "The Safety of available immunotherapy for the treatment of glioblastoma." Expert opinion on drug safety 16.3 (March 2017): 277-287.
PMID
27989218
Source
epmc
Published In
Expert Opinion on Drug Safety
Volume
16
Issue
3
Publish Date
2017
Start Page
277
End Page
287
DOI
10.1080/14740338.2017.1273898

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles.

While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.

Authors
Sayour, EJ; De Leon, G; Pham, C; Grippin, A; Kemeny, H; Chua, J; Huang, J; Sampson, JH; Sanchez-Perez, L; Flores, C; Mitchell, DA
MLA Citation
Sayour, EJ, De Leon, G, Pham, C, Grippin, A, Kemeny, H, Chua, J, Huang, J, Sampson, JH, Sanchez-Perez, L, Flores, C, and Mitchell, DA. "Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles." Oncoimmunology 6.1 (January 2017): e1256527-.
PMID
28197373
Source
epmc
Published In
OncoImmunology
Volume
6
Issue
1
Publish Date
2017
Start Page
e1256527
DOI
10.1080/2162402x.2016.1256527

Advances and challenges: dendritic cell vaccination strategies for glioblastoma.

Glioblastoma is the most common primary brain tumor in adults and prognosis remains poor with a median survival of approximately 15-17 months. This review provides an overview of recent advances in the field of glioblastoma immunotherapy. Areas covered: Recent advances in dendritic cell vaccination immunotherapy are showing encouraging results in clinical trials and promise to extend patient survival. In this report we discuss current scientific knowledge regarding dendritic cell (DC) vaccines, including approaches to differentiating, priming, and injecting dendritic cells to achieve maximal anti-tumor efficacy in glioblastoma. These findings are compared to recently completed and currently ongoing glioblastoma clinical trials. Novel methods such as 'fastDCs' and vaccines targeting DCs in-vivo may offer more effective treatment when compared to traditional DC vaccines and have already entered the clinic. Expert commentary: Finally, we discuss the challenges of T-cell dysfunctions caused by glioblastoma immunosuppression and how they affect dendritic cell vaccinations approaches.

Authors
Schaller, TH; Sampson, JH
MLA Citation
Schaller, TH, and Sampson, JH. "Advances and challenges: dendritic cell vaccination strategies for glioblastoma." Expert review of vaccines 16.1 (January 2017): 27-36.
PMID
27500911
Source
epmc
Published In
Expert Review of Vaccines
Volume
16
Issue
1
Publish Date
2017
Start Page
27
End Page
36

The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial.

Pediatric surgical trials are rare and the impact of such trials on the institutions in which they are conducted is unknown. The purpose of this study was to analyze the clinical and financial impact of The Re-MATCH trial, a Phase I clinical trial requiring the biopsy or resection of recurrent medulloblastoma or PNET for enrollment. Inpatient financial and clinical volume information was collected during the 3 years of trial enrollment and the years preceding and following it. The primary endpoints were the difference in direct contribution margin (DCM), or net gain, of study and non-study patients and the difference in surgical volume during the study and non-study periods. The trial enrolled 18 patients; 15 had surgery at the sponsor institution and three had surgery at their home institution, then transferred tumor material to the sponsor institution. There were no differences between the two groups for potentially confounding variables such as neurosurgical procedure work relative value units (P = 0.13) or insurance provider (P = 0.26). There was no difference between the inpatient DCM per case for the institution for non-study patients (mean ± SD, $9039 ± $28,549) and study patients ($14,332 ± $20,231) (P = 0.4819). During the non-study period, there were a mean of 2.78 ± 1.65 pediatric brain tumor resections per month compared to 3.34 ± 1.66 cases per month during the study period, a 17% increase. When the 15 study patients were excluded, there were 2.97 ± 1.64 cases per month, a 7% increase. However, this increase in total case volume including study and non-study patients was not significant (P = 0.121). Phase I investigator-initiated surgically-based clinical trials may increase institutional surgical volume without imposing a financial burden. Finances are unlikely to be a barrier for researchers negotiating for resources to conduct such trials.

Authors
Thompson, EM; Gururangan, S; Grant, G; Mitchell, D; Sampson, JH
MLA Citation
Thompson, EM, Gururangan, S, Grant, G, Mitchell, D, and Sampson, JH. "The clinical and financial impact of a pediatric surgical neuro-oncology clinical trial." Journal of neuro-oncology (November 18, 2016).
PMID
27864705
Source
epmc
Published In
Journal of Neuro-Oncology
Publish Date
2016

Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity.

Oncolytic viruses, proteasome inhibitors, and natural killer (NK)-cell immunotherapy have all been studied extensively as monotherapies but have never been evaluated in combination. Synergetic treatment of oncolytic virus-infected glioblastomas with a proteasome inhibitor induces necroptotic cell death to enhance NK-cell immunotherapy, prolonging survival against human glioblastoma. Clin Cancer Res; 22(21); 5164-6. ©2016 AACRSee related article by Yoo et al., p. 5265.

Authors
Suryadevara, CM; Riccione, KA; Sampson, JH
MLA Citation
Suryadevara, CM, Riccione, KA, and Sampson, JH. "Immunotherapy Gone Viral: Bortezomib and oHSV Enhance Antitumor NK-Cell Activity." Clinical cancer research : an official journal of the American Association for Cancer Research 22.21 (November 2016): 5164-5166.
PMID
27521450
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
21
Publish Date
2016
Start Page
5164
End Page
5166
DOI
10.1158/1078-0432.ccr-16-1666

Rapid Reprogramming of Primary Human Astrocytes into Potent Tumor-Initiating Cells with Defined Genetic Factors.

Cancer stem-like cells (CSC) are thought to drive brain cancer, but their cellular and molecular origins remain uncertain. Here, we report the successful generation of induced CSC (iCSC) from primary human astrocytes through the expression of defined genetic factors. Combined transduction of four factors, Myc, Oct-4, p53DD, and Ras, induced efficient transformation of primary human astrocytes into malignant cells with powerful tumor-initiating capabilities. Notably, transplantation of 100 transduced cells into nude mice was sufficient for tumor formation. The cells showed unlimited self-renewal ability with robust telomerase activities. In addition, they expressed typical glioma stem-like cell markers, such as CD133, CD15, and CD90. Moreover, these cells could form spheres in culture and differentiate into neuron-like, astrocyte-like, and oligodendrocyte-like cells. Finally, they also displayed resistance to the widely used brain cancer drug temozolomide. These iCSCs could provide important tools for studies of glioma biology and therapeutics development. Cancer Res; 76(17); 5143-50. ©2016 AACR.

Authors
Li, F; Liu, X; Sampson, JH; Bigner, DD; Li, C-Y
MLA Citation
Li, F, Liu, X, Sampson, JH, Bigner, DD, and Li, C-Y. "Rapid Reprogramming of Primary Human Astrocytes into Potent Tumor-Initiating Cells with Defined Genetic Factors." Cancer research 76.17 (September 2016): 5143-5150.
PMID
27364552
Source
epmc
Published In
Cancer Research
Volume
76
Issue
17
Publish Date
2016
Start Page
5143
End Page
5150
DOI
10.1158/0008-5472.can-16-0171

Advances in Immunotherapy: Abhijit Guha Award Presentation.

Authors
Sampson, JH
MLA Citation
Sampson, JH. "Advances in Immunotherapy: Abhijit Guha Award Presentation." August 2016.
PMID
27399370
Source
epmc
Published In
Neurosurgery
Volume
63 Suppl 1
Publish Date
2016
Start Page
85
End Page
87
DOI
10.1227/neu.0000000000001286

Delivering therapy to target: improving the odds for successful drug development.

The direct delivery of drugs and other agents into tissue (in contrast to systemic administration) has been used in clinical trials for brain cancer, neurodegenerative diseases and peripheral tumors. However, continuing evidence suggests that clinical efficacy depends on adequate delivery to a target. Inadequate delivery may have doomed otherwise effective drugs, through failure to distinguish drug inefficacy from poor distribution at the target. Conventional pretreatment clinical images of the patient fail to reveal the complexity and diversity of drug transport pathways in tissue. We discuss the richness of these pathways and argue that development and patient treatment can be sped up and improved by: using quantitative as well as 'real-time' imaging; customized simulations using data from that imaging; and device designs that optimize the drug-device combination.

Authors
Raghavan, R; Brady, ML; Sampson, JH
MLA Citation
Raghavan, R, Brady, ML, and Sampson, JH. "Delivering therapy to target: improving the odds for successful drug development." Therapeutic delivery 7.7 (July 2016): 457-481.
PMID
27403630
Source
epmc
Published In
Therapeutic delivery
Volume
7
Issue
7
Publish Date
2016
Start Page
457
End Page
481
DOI
10.4155/tde-2016-0016

Emerging immunotherapies for glioblastoma.

Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.

Authors
Desai, R; Suryadevara, CM; Batich, KA; Farber, SH; Sanchez-Perez, L; Sampson, JH
MLA Citation
Desai, R, Suryadevara, CM, Batich, KA, Farber, SH, Sanchez-Perez, L, and Sampson, JH. "Emerging immunotherapies for glioblastoma." Expert opinion on emerging drugs 21.2 (June 2016): 133-145.
PMID
27223671
Source
epmc
Published In
Expert Opinion on Emerging Drugs
Volume
21
Issue
2
Publish Date
2016
Start Page
133
End Page
145
DOI
10.1080/14728214.2016.1186643

Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice.Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment.This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment.

Authors
Pham, CD; Flores, C; Yang, C; Pinheiro, EM; Yearley, JH; Sayour, EJ; Pei, Y; Moore, C; McLendon, RE; Huang, J; Sampson, JH; Wechsler-Reya, R; Mitchell, DA
MLA Citation
Pham, CD, Flores, C, Yang, C, Pinheiro, EM, Yearley, JH, Sayour, EJ, Pei, Y, Moore, C, McLendon, RE, Huang, J, Sampson, JH, Wechsler-Reya, R, and Mitchell, DA. "Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma." Clinical cancer research : an official journal of the American Association for Cancer Research 22.3 (February 2016): 582-595.
PMID
26405194
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
22
Issue
3
Publish Date
2016
Start Page
582
End Page
595
DOI
10.1158/1078-0432.ccr-15-0713

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy.

Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.

Authors
Saraswathula, A; Reap, EA; Choi, BD; Schmittling, RJ; Norberg, PK; Sayour, EJ; Herndon, JE; Healy, P; Congdon, KL; Archer, GE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Saraswathula, A, Reap, EA, Choi, BD, Schmittling, RJ, Norberg, PK, Sayour, EJ, Herndon, JE, Healy, P, Congdon, KL, Archer, GE, Sanchez-Perez, L, and Sampson, JH. "Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy." Cancer immunology, immunotherapy : CII 65.2 (February 2016): 205-211.
PMID
26759007
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
65
Issue
2
Publish Date
2016
Start Page
205
End Page
211
DOI
10.1007/s00262-015-1784-3

Preconditioning Vaccine Sites for mRNA-Transfected Dendritic Cell Therapy and Antitumor Efficacy.

Messenger RNA (mRNA)-transfected dendritic cell (DC) vaccines have been shown to be a powerful modality for eliciting antitumor immune responses in mice and humans; however, their application has not been fully optimized since many of the factors that contribute to their efficacy remain poorly understood. Work stemming from our laboratory has recently demonstrated that preconditioning the vaccine site with a recall antigen prior to the administration of a dendritic cell vaccine creates systemic recall responses and resultantly enhances dendritic cell migration to the lymph nodes with improved antitumor efficacy. This chapter describes the generation of murine mRNA-transfected DC vaccines, as well as a method for vaccine site preconditioning with protein antigen formulations that create potent recall responses.

Authors
Batich, KA; Swartz, AM; Sampson, JH
MLA Citation
Batich, KA, Swartz, AM, and Sampson, JH. "Preconditioning Vaccine Sites for mRNA-Transfected Dendritic Cell Therapy and Antitumor Efficacy." January 2016. 819-838.
PMID
27076169
Source
epmc
Volume
1403
Publish Date
2016
Start Page
819
End Page
838
DOI
10.1007/978-1-4939-3387-7_47

Peptide vaccines for the treatment of glioblastoma

© 2014, Springer Science+Business Media New York.Glioblastoma multiforme (GBM) is an extremely malignant brain tumor for which current therapies do little to remedy. Despite aggressive treatment with surgery, radiation therapy, and chemotherapy, tumors inevitably recur as a direct consequence of the infiltrative nature of GBM. The poor prognosis of patients with GBM underscores the clear and urgent need for more precise and potent therapies. Immunotherapy is emerging as a promising means to treat GBM based on the immune system’s capacity to mediate tumor-specific cytotoxicity. In this review, we will discuss the use of peptide vaccines for the treatment of GBM. The simplicity of peptide vaccines and their ability to elicit tumor antigen-specific immune responses make them an invaluable tool for the study of brain tumor immunotherapy.

Authors
Swartz, AM; Batich, KA; Fecci, PE; Sampson, JH
MLA Citation
Swartz, AM, Batich, KA, Fecci, PE, and Sampson, JH. "Peptide vaccines for the treatment of glioblastoma." Journal of Neuro-Oncology 123.3 (December 10, 2015): 433-440. (Review)
Source
scopus
Published In
Journal of Neuro-Oncology
Volume
123
Issue
3
Publish Date
2015
Start Page
433
End Page
440
DOI
10.1007/s11060-014-1676-y

Alternating Electric Fields for the Treatment of Glioblastoma.

Authors
Sampson, JH
MLA Citation
Sampson, JH. "Alternating Electric Fields for the Treatment of Glioblastoma." JAMA 314.23 (December 2015): 2511-2513.
PMID
26670969
Source
epmc
Published In
JAMA : the journal of the American Medical Association
Volume
314
Issue
23
Publish Date
2015
Start Page
2511
End Page
2513
DOI
10.1001/jama.2015.16701

Vaccination strategies for neuro-oncology.

Vaccination against cancer-associated antigens has long held the promise of inducting potent antitumor immunity, targeted cytotoxicity while sparing normal tissues, and long-lasting immunologic memory that can provide surveillance against tumor recurrence. Evaluation of vaccination strategies in preclinical brain tumor models has borne out the capacity for the immune system to effectively and safely eradicate established tumors within the central nervous system. Early phase clinical trials have established the feasibility, safety, and immunogenicity of several vaccine platforms, predominantly in patients with glioblastoma. Definitive demonstration of clinical benefit awaits further study, but initial results have been encouraging. With increased understanding of the stimulatory and regulatory pathways that govern immunologic responses and the enhanced capacity to identify novel antigenic targets using genomic interrogation of tumor cells, vaccination platforms for patients with malignant brain tumors are advancing with increasing personalized complexity and integration into combinatorial treatment paradigms.

Authors
Sampson, JH; Mitchell, DA
MLA Citation
Sampson, JH, and Mitchell, DA. "Vaccination strategies for neuro-oncology." Neuro-oncology 17 Suppl 7 (November 2015): vii15-vii25. (Review)
PMID
26516221
Source
epmc
Published In
Neuro-Oncology
Volume
17 Suppl 7
Publish Date
2015
Start Page
vii15
End Page
vii25
DOI
10.1093/neuonc/nov159

Immunotherapy response assessment in neuro-oncology: a report of the RANO working group.

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate.

Authors
Okada, H; Weller, M; Huang, R; Finocchiaro, G; Gilbert, MR; Wick, W; Ellingson, BM; Hashimoto, N; Pollack, IF; Brandes, AA; Franceschi, E; Herold-Mende, C; Nayak, L; Panigrahy, A; Pope, WB; Prins, R; Sampson, JH; Wen, PY; Reardon, DA
MLA Citation
Okada, H, Weller, M, Huang, R, Finocchiaro, G, Gilbert, MR, Wick, W, Ellingson, BM, Hashimoto, N, Pollack, IF, Brandes, AA, Franceschi, E, Herold-Mende, C, Nayak, L, Panigrahy, A, Pope, WB, Prins, R, Sampson, JH, Wen, PY, and Reardon, DA. "Immunotherapy response assessment in neuro-oncology: a report of the RANO working group." The Lancet. Oncology 16.15 (November 2015): e534-e542. (Review)
PMID
26545842
Source
epmc
Published In
The Lancet Oncology
Volume
16
Issue
15
Publish Date
2015
Start Page
e534
End Page
e542
DOI
10.1016/s1470-2045(15)00088-1

Patient validation of retrospective data.

Authors
Babu, R; Sampson, JH
MLA Citation
Babu, R, and Sampson, JH. "Patient validation of retrospective data." Journal of neurosurgery 123.4 (October 2015): 969-970.
PMID
26252462
Source
epmc
Published In
Journal of neurosurgery
Volume
123
Issue
4
Publish Date
2015
Start Page
969
End Page
970
DOI
10.3171/2015.3.jns142959

Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.

Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80%) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75%). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60%) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40%) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.

Authors
Nair, SK; Driscoll, T; Boczkowski, D; Schmittling, R; Reynolds, R; Johnson, LA; Grant, G; Fuchs, H; Bigner, DD; Sampson, JH; Gururangan, S; Mitchell, DA
MLA Citation
Nair, SK, Driscoll, T, Boczkowski, D, Schmittling, R, Reynolds, R, Johnson, LA, Grant, G, Fuchs, H, Bigner, DD, Sampson, JH, Gururangan, S, and Mitchell, DA. "Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma." Journal of neuro-oncology 125.1 (October 2015): 65-74.
PMID
26311248
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
125
Issue
1
Publish Date
2015
Start Page
65
End Page
74
DOI
10.1007/s11060-015-1890-2

Editorial: Not everything that matters can be measured and not everything that can be measured matters.

Authors
Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Choi, BD, Fecci, PE, and Sampson, JH. "Editorial: Not everything that matters can be measured and not everything that can be measured matters." Journal of neurosurgery 123.3 (September 2015): 543-544.
PMID
26115465
Source
epmc
Published In
Journal of neurosurgery
Volume
123
Issue
3
Publish Date
2015
Start Page
543
End Page
544
DOI
10.3171/2015.2.jns142977

Prospects of immune checkpoint modulators in the treatment of glioblastoma.

Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15-17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

Authors
Preusser, M; Lim, M; Hafler, DA; Reardon, DA; Sampson, JH
MLA Citation
Preusser, M, Lim, M, Hafler, DA, Reardon, DA, and Sampson, JH. "Prospects of immune checkpoint modulators in the treatment of glioblastoma." Nature reviews. Neurology 11.9 (September 2015): 504-514. (Review)
PMID
26260659
Source
epmc
Published In
Nature Reviews Neurology
Volume
11
Issue
9
Publish Date
2015
Start Page
504
End Page
514
DOI
10.1038/nrneurol.2015.139

Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma.

Authors
Vlahovic, G; Fecci, PE; Reardon, D; Sampson, JH
MLA Citation
Vlahovic, G, Fecci, PE, Reardon, D, and Sampson, JH. "Programmed death ligand 1 (PD-L1) as an immunotherapy target in patients with glioblastoma." Neuro-oncology 17.8 (August 2015): 1043-1045.
PMID
25964311
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
8
Publish Date
2015
Start Page
1043
End Page
1045
DOI
10.1093/neuonc/nov071

Peptide vaccines for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) is an extremely malignant brain tumor for which current therapies do little to remedy. Despite aggressive treatment with surgery, radiation therapy, and chemotherapy, tumors inevitably recur as a direct consequence of the infiltrative nature of GBM. The poor prognosis of patients with GBM underscores the clear and urgent need for more precise and potent therapies. Immunotherapy is emerging as a promising means to treat GBM based on the immune system's capacity to mediate tumor-specific cytotoxicity. In this review, we will discuss the use of peptide vaccines for the treatment of GBM. The simplicity of peptide vaccines and their ability to elicit tumor antigen-specific immune responses make them an invaluable tool for the study of brain tumor immunotherapy.

Authors
Swartz, AM; Batich, KA; Fecci, PE; Sampson, JH
MLA Citation
Swartz, AM, Batich, KA, Fecci, PE, and Sampson, JH. "Peptide vaccines for the treatment of glioblastoma." Journal of neuro-oncology 123.3 (July 2015): 433-440.
PMID
25491947
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
123
Issue
3
Publish Date
2015
Start Page
433
End Page
440
DOI
10.1007/s11060-014-1676-y

A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study.

The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation.Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy.This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.

Authors
Schuster, J; Lai, RK; Recht, LD; Reardon, DA; Paleologos, NA; Groves, MD; Mrugala, MM; Jensen, R; Baehring, JM; Sloan, A; Archer, GE; Bigner, DD; Cruickshank, S; Green, JA; Keler, T; Davis, TA; Heimberger, AB; Sampson, JH
MLA Citation
Schuster, J, Lai, RK, Recht, LD, Reardon, DA, Paleologos, NA, Groves, MD, Mrugala, MM, Jensen, R, Baehring, JM, Sloan, A, Archer, GE, Bigner, DD, Cruickshank, S, Green, JA, Keler, T, Davis, TA, Heimberger, AB, and Sampson, JH. "A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study." Neuro-oncology 17.6 (June 2015): 854-861.
PMID
25586468
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
6
Publish Date
2015
Start Page
854
End Page
861
DOI
10.1093/neuonc/nou348

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; Mclendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, Mclendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development." Journal of neurochemistry 133.5 (June 2015): 730-738.
PMID
25598002
Source
epmc
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Editorial: Turning fluorescence into black and white.

Authors
Fecci, PE; Babu, R; Adamson, DC; Sampson, JH
MLA Citation
Fecci, PE, Babu, R, Adamson, DC, and Sampson, JH. "Editorial: Turning fluorescence into black and white." Journal of neurosurgery 122.6 (June 2015): 1356-1358.
PMID
25839932
Source
epmc
Published In
Journal of neurosurgery
Volume
122
Issue
6
Publish Date
2015
Start Page
1356
End Page
1358
DOI
10.3171/2014.10.jns141788

Tetanus toxoid conditioning enhances migration and efficacy of dendritic cell vaccines in patients with glioblastoma

Authors
Batich, K; Sampson, JH; Reap, E; Sanchez-Perez, L; Archer, G; Snyder, D; Nair, S; Gunn, M; Mitchell, D
MLA Citation
Batich, K, Sampson, JH, Reap, E, Sanchez-Perez, L, Archer, G, Snyder, D, Nair, S, Gunn, M, and Mitchell, D. "Tetanus toxoid conditioning enhances migration and efficacy of dendritic cell vaccines in patients with glioblastoma." June 2015.
Source
wos-lite
Published In
Journal of neurosurgery
Volume
122
Issue
6
Publish Date
2015
Start Page
A1522
End Page
A1522

Are BiTEs the "missing link" in cancer therapy?

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.

Authors
Suryadevara, CM; Gedeon, PC; Sanchez-Perez, L; Verla, T; Alvarez-Breckenridge, C; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, CM, Gedeon, PC, Sanchez-Perez, L, Verla, T, Alvarez-Breckenridge, C, Choi, BD, Fecci, PE, and Sampson, JH. "Are BiTEs the "missing link" in cancer therapy?." Oncoimmunology 4.6 (June 2015): e1008339-. (Review)
PMID
26155413
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
6
Publish Date
2015
Start Page
e1008339
DOI
10.1080/2162402x.2015.1008339

Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143.

Authors
Sampson, JH; Vlahovic, G; Sahebjam, S; Omuro, AMP; Baehring, JM; Hafler, DA; Voloschin, AD; Paliwal, P; Grosso, J; Coric, V; Cloughesy, TF; Lim, M; Reardon, DA
MLA Citation
Sampson, JH, Vlahovic, G, Sahebjam, S, Omuro, AMP, Baehring, JM, Hafler, DA, Voloschin, AD, Paliwal, P, Grosso, J, Coric, V, Cloughesy, TF, Lim, M, and Reardon, DA. "Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Lally-Goss, D; Reap, E; Desjardins, A; Peters, KB; Randazzo, D; Healy, P; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, G, Archer, GE, Lally-Goss, D, Reap, E, Desjardins, A, Peters, KB, Randazzo, D, Healy, P, Herndon, JE, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Vlahovic, G; Randazzo, D; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, ES; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Vlahovic, G, Randazzo, D, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Lipp, ES, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma

Authors
Reardon, DA; Schuster, J; Tran, DD; Fink, KL; Nabors, LB; Li, G; Bota, DA; Lukas, RV; Desjardins, A; Ashby, LS; Duic, JP; Mrugala, MM; Werner, A; Hawthorne, T; He, Y; Green, JA; Yellin, MJ; Turner, CD; Davis, TA; Sampson, JH; Grp, RS
MLA Citation
Reardon, DA, Schuster, J, Tran, DD, Fink, KL, Nabors, LB, Li, G, Bota, DA, Lukas, RV, Desjardins, A, Ashby, LS, Duic, JP, Mrugala, MM, Werner, A, Hawthorne, T, He, Y, Green, JA, Yellin, MJ, Turner, CD, Davis, TA, Sampson, JH, and Grp, RS. "ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide.

Therapeutic vaccination of patients with cancer-targeting tumor-associated antigens is a promising strategy for the specific eradication of invasive malignancies with minimal toxicity to normal tissues. However, as increasingly potent modalities for stimulating immunologic responses are developed for clinical evaluation, the risk of inflammatory and autoimmune toxicities also may be exacerbated. In this report, we describe the induction of a severe (grade 3) immunologic reaction in a patient with newly diagnosed glioblastoma (GBM) receiving autologous RNA-pulsed dendritic cell (DC) vaccines admixed with GM-CSF and administered coordinately with cycles of dose-intensified temozolomide. Shortly after the eighth administration of the admixed intradermal vaccine, the patient experienced dizziness, flushing, conjunctivitis, headache, and the outbreak of a disseminated macular/papular rash and bilateral indurated injection sites. Immunologic workup of patient reactivity revealed sensitization to the GM-CSF component of the vaccine and the production of high levels of anti-GM-CSF autoantibodies during vaccination. Removal of GM-CSF from the DC vaccine allowed continued vaccination without incident. Despite the known lymphodepletive and immunosuppressive effects of temozolomide, these observations demonstrate the capacity for the generation of severe immunologic reactivity in patients with GBM receiving DC-based therapy during adjuvant dose-intensified temozolomide.

Authors
Mitchell, DA; Sayour, EJ; Reap, E; Schmittling, R; DeLeon, G; Norberg, P; Desjardins, A; Friedman, AH; Friedman, HS; Archer, G; Sampson, JH
MLA Citation
Mitchell, DA, Sayour, EJ, Reap, E, Schmittling, R, DeLeon, G, Norberg, P, Desjardins, A, Friedman, AH, Friedman, HS, Archer, G, and Sampson, JH. "Severe adverse immunologic reaction in a patient with glioblastoma receiving autologous dendritic cell vaccines combined with GM-CSF and dose-intensified temozolomide." Cancer immunology research 3.4 (April 2015): 320-325.
PMID
25387895
Source
epmc
Published In
Cancer Immunology Research
Volume
3
Issue
4
Publish Date
2015
Start Page
320
End Page
325
DOI
10.1158/2326-6066.cir-14-0100

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Authors
Sayour, EJ; McLendon, P; McLendon, R; De Leon, G; Reynolds, R; Kresak, J; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, McLendon, R, De Leon, G, Reynolds, R, Kresak, J, Sampson, JH, and Mitchell, DA. "Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma." Cancer immunology, immunotherapy : CII 64.4 (April 2015): 419-427.
PMID
25555571
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
4
Publish Date
2015
Start Page
419
End Page
427
DOI
10.1007/s00262-014-1651-7

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Batich, KA, Gunn, MD, Huang, M-N, Sanchez-Perez, L, Nair, SK, Congdon, KL, Reap, EA, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (March 11, 2015): 366-369.
PMID
25762141
Source
epmc
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4(+) and CD8(+) tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, DD, Sampson, J, and Mitchell, DA. "Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas." Oncoimmunology 4.3 (March 2015): e994374-.
PMID
25949916
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e994374
DOI
10.4161/2162402x.2014.994374

miR-23a blockade enhances adoptive T cell transfer therapy by preserving immune-competence in the tumor microenvironment.

In adoptive T cell transfer therapy (ACT), the antitumor efficacy of cytotoxic CD8(+) T lymphocytes (CTLs) has been limited by tumor-induced immunosuppression. We have demonstrated that miR-23a blockade in tumor-specific CTLs conferred resilience to TGFβ-mediated immunosuppression, resulting in superior tumor control. Our studies highlight miR-23a in tumor-specific CTLs as a clinically relevant target to enhance ACT.

Authors
Lin, R; Sampson, JH; Li, Q-J; Zhu, B
MLA Citation
Lin, R, Sampson, JH, Li, Q-J, and Zhu, B. "miR-23a blockade enhances adoptive T cell transfer therapy by preserving immune-competence in the tumor microenvironment." Oncoimmunology 4.3 (March 2015): e990803-.
PMID
25949909
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e990803
DOI
10.4161/2162402x.2014.990803

Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care.

Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care.

Authors
Riccione, K; Suryadevara, CM; Snyder, D; Cui, X; Sampson, JH; Sanchez-Perez, L
MLA Citation
Riccione, K, Suryadevara, CM, Snyder, D, Cui, X, Sampson, JH, and Sanchez-Perez, L. "Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care." Journal of visualized experiments : JoVE 96 (February 16, 2015).
PMID
25741761
Source
epmc
Published In
Journal of Visualized Experiments
Issue
96
Publish Date
2015
DOI
10.3791/52397

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma

© 2014, Springer-Verlag Berlin Heidelberg.Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate lymphocyte subpopulations allowing for high-throughput analysis and bypassing manual selection bias. As shown in previous studies, enumeration of individual lymphocyte populations did not correlate with clinical outcomes in patients with GBM. However, the CD4+ to regulatory FoxP3+ T cell ratio was diminished in recurrent disease, and increased CD3 and CD8+ to regulatory T cell ratios showed a positive correlation with survival outcomes in primary GBM. These results suggest that while absolute numbers of tumor infiltrating lymphocytes may not be informative for predicting clinical outcomes in patients with GBM, the effective balance of CD3, CD4 and CD8+ T cells to immunosuppressive FoxP3+ regulatory cells may influence clinical outcomes in this patient population.

Authors
Sayour, EJ; McLendon, P; McLendon, R; De Leon, G; Reynolds, R; Kresak, J; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, McLendon, R, De Leon, G, Reynolds, R, Kresak, J, Sampson, JH, and Mitchell, DA. "Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma." Cancer Immunology, Immunotherapy 64.4 (January 1, 2015): 419-427.
Source
scopus
Published In
Cancer Immunology, Immunotherapy
Volume
64
Issue
4
Publish Date
2015
Start Page
419
End Page
427
DOI
10.1007/s00262-014-1651-7

Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma.

INTRODUCTION: Patients with primary glioblastoma (GBM) have a dismal prognosis despite standard therapy, which can induce potentially deleterious side effects. Arming the immune system is an alternative therapeutic approach, as its cellular effectors and inherent capacity for memory can be utilized to specifically target invasive tumor cells, while sparing collateral damage to otherwise healthy brain parenchyma. AREAS COVERED: Active immunotherapy is aimed at eliciting a specific immune response against tumor antigens. Dendritic cells (DCs) are one of the most potent activators of de novo and recall immune responses and are thus a vehicle for successful immunotherapy. Currently, investigators are optimizing DC vaccines by enhancing maturation status and migratory potential to induce more potent antitumor responses. An update on the most recent DC immunotherapy trials is provided. EXPERT OPINION: Targeting of unique antigens restricted to the tumor itself is the most important parameter in advancing DC vaccines. In order to overcome intrinsic mechanisms of immune evasion observed in GBM, the future of DC-based therapy lies in a multi-antigenic vaccine approach. Successful targeting of multiple antigens will require a comprehensive understanding of all immunologically relevant oncological epitopes present in each tumor, thereby permitting a rational vaccine design.

Authors
Batich, KA; Swartz, AM; Sampson, JH
MLA Citation
Batich, KA, Swartz, AM, and Sampson, JH. "Enhancing dendritic cell-based vaccination for highly aggressive glioblastoma." Expert opinion on biological therapy 15.1 (January 2015): 79-94.
PMID
25327832
Source
epmc
Published In
Expert Opinion on Biological Therapy
Volume
15
Issue
1
Publish Date
2015
Start Page
79
End Page
94
DOI
10.1517/14712598.2015.972361

Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trial.

PURPOSE: To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. METHODS AND MATERIALS: Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board-approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator-based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). RESULTS: Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non-small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P<.01), and GTV was similar (P=.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P=.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P=.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. CONCLUSIONS: SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate.

Authors
Kirkpatrick, JP; Wang, Z; Sampson, JH; McSherry, F; Herndon, JE; Allen, KJ; Duffy, E; Hoang, JK; Chang, Z; Yoo, DS; Kelsey, CR; Yin, F-F
MLA Citation
Kirkpatrick, JP, Wang, Z, Sampson, JH, McSherry, F, Herndon, JE, Allen, KJ, Duffy, E, Hoang, JK, Chang, Z, Yoo, DS, Kelsey, CR, and Yin, F-F. "Defining the optimal planning target volume in image-guided stereotactic radiosurgery of brain metastases: results of a randomized trial." International journal of radiation oncology, biology, physics 91.1 (January 2015): 100-108.
PMID
25442342
Source
epmc
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
91
Issue
1
Publish Date
2015
Start Page
100
End Page
108
DOI
10.1016/j.ijrobp.2014.09.004

Immunotherapy for malignant glioma.

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

Authors
Suryadevara, CM; Verla, T; Sanchez-Perez, L; Reap, EA; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, CM, Verla, T, Sanchez-Perez, L, Reap, EA, Choi, BD, Fecci, PE, and Sampson, JH. "Immunotherapy for malignant glioma." Surgical neurology international 6.Suppl 1 (January 2015): S68-S77.
PMID
25722935
Source
epmc
Published In
Surgical Neurology International
Volume
6
Issue
Suppl 1
Publish Date
2015
Start Page
S68
End Page
S77
DOI
10.4103/2152-7806.151341

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development

© 2015 International Society for Neurochemistry.The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; McLendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, McLendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development." Journal of Neurochemistry 133.5 (2015): 730-738.
Source
scival
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression.

CD8(+) cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by the susceptibility of ex vivo-expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β-mediated tumor immune-evasion pathway.

Authors
Lin, R; Chen, L; Chen, G; Hu, C; Jiang, S; Sevilla, J; Wan, Y; Sampson, JH; Zhu, B; Li, Q-J
MLA Citation
Lin, R, Chen, L, Chen, G, Hu, C, Jiang, S, Sevilla, J, Wan, Y, Sampson, JH, Zhu, B, and Li, Q-J. "Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression." The Journal of clinical investigation 124.12 (December 2014): 5352-5367.
PMID
25347474
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
12
Publish Date
2014
Start Page
5352
End Page
5367
DOI
10.1172/jci76561

Oncolytic polio virotherapy of cancer.

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (November 2014): 3277-3286. (Review)
PMID
24939611
Source
epmc
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Immunotherapy advances for glioblastoma.

Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.

Authors
Reardon, DA; Freeman, G; Wu, C; Chiocca, EA; Wucherpfennig, KW; Wen, PY; Fritsch, EF; Curry, WT; Sampson, JH; Dranoff, G
MLA Citation
Reardon, DA, Freeman, G, Wu, C, Chiocca, EA, Wucherpfennig, KW, Wen, PY, Fritsch, EF, Curry, WT, Sampson, JH, and Dranoff, G. "Immunotherapy advances for glioblastoma." Neuro-oncology 16.11 (November 2014): 1441-1458. (Review)
PMID
25190673
Source
epmc
Published In
Neuro-Oncology
Volume
16
Issue
11
Publish Date
2014
Start Page
1441
End Page
1458
DOI
10.1093/neuonc/nou212

Immunotherapy for primary brain tumors: no longer a matter of privilege.

Immunotherapy for cancer continues to gain both momentum and legitimacy as a rational mode of therapy and a vital treatment component in the emerging era of personalized medicine. Gliomas, and their most malignant form, glioblastoma, remain as a particularly devastating solid tumor for which standard treatment options proffer only modest efficacy and target specificity. Immunotherapy would seem a well-suited choice to address such deficiencies given both the modest inherent immunogenicity of gliomas and the strong desire for treatment specificity within the confines of the toxicity-averse normal brain. This review highlights the caveats and challenges to immunotherapy for primary brain tumors, as well as reviewing modalities that are currently used or are undergoing active investigation. Tumor immunosuppressive countermeasures, peculiarities of central nervous system immune access, and opportunities for rational treatment design are discussed.

Authors
Fecci, PE; Heimberger, AB; Sampson, JH
MLA Citation
Fecci, PE, Heimberger, AB, and Sampson, JH. "Immunotherapy for primary brain tumors: no longer a matter of privilege." Clinical cancer research : an official journal of the American Association for Cancer Research 20.22 (November 2014): 5620-5629. (Review)
PMID
25398845
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
22
Publish Date
2014
Start Page
5620
End Page
5629
DOI
10.1158/1078-0432.ccr-14-0832

Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, A; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, A, Friedman, HS, Bigner, DD, and Gromeier, M. "Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
CT416
End Page
CT416
DOI
10.1158/1538-7445.AM2014-CT416

Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens.

Malignant gliomas (MGs) represent the most common primary brain tumors in adults, the most deadly of which is grade IV glioblastoma. Patients with glioblastoma undergoing current standard-of-care therapy have a median survival of 12 - 15 months.Over the past 25 years, there have been modest advancements in the treatment of MGs. Assessment of therapeutic responses has continued to evolve to account for the increasing number of agents being tested in the clinic. Currently approved therapies for primary tumors have been extended for use in the setting of recurrent disease with modest efficacy. Agents initially approved for recurrent gliomas have begun to demonstrate efficacy against de novo tumors but will ultimately need to be evaluated in future studies for scheduling, timing and dosing relative to chemotherapy.Screening and identification of tumor-specific mutations is critical for the advancement of effective therapy that is both safe and precise for the patient. Two unique antigens found in glioblastoma are currently being employed as targets for immunotherapeutic vaccines, one of which has advanced to Phase III testing. Whole genome sequencing of MGs has yielded two other novel mutations that offer great promise for the development of molecular inhibitors.

Authors
Batich, KA; Sampson, JH
MLA Citation
Batich, KA, and Sampson, JH. "Standard of care and future pharmacological treatment options for malignant glioma: an urgent need for screening and identification of novel tumor-specific antigens." Expert opinion on pharmacotherapy 15.14 (October 2014): 2047-2061. (Review)
PMID
25139628
Source
epmc
Published In
Expert Opinion on Pharmacotherapy
Volume
15
Issue
14
Publish Date
2014
Start Page
2047
End Page
2061
DOI
10.1517/14656566.2014.947266

Recurrent malignant gliomas.

In almost all patients, malignant glioma recurs following initial treatment with maximal safe resection, conformal radiotherapy, and temozolomide. This review describes the many options for treatment of recurrent malignant gliomas, including reoperation, alternating electric field therapy, chemotherapy, stereotactic radiotherapy or radiosurgery, or some combination of these modalities, presenting the evidence for each approach. No standard of care has been established, though the antiangiogenic agent, bevacizumab; stereotactic radiotherapy or radiosurgery; and, perhaps, combined treatment with these 2 modalities appear to offer modest benefits over other approaches. Clearly, randomized trials of these options would be advantageous, and novel, more efficacious approaches are urgently needed.

Authors
Kirkpatrick, JP; Sampson, JH
MLA Citation
Kirkpatrick, JP, and Sampson, JH. "Recurrent malignant gliomas." Seminars in radiation oncology 24.4 (October 2014): 289-298. (Review)
PMID
25219814
Source
epmc
Published In
Seminars in Radiation Oncology
Volume
24
Issue
4
Publish Date
2014
Start Page
289
End Page
298
DOI
10.1016/j.semradonc.2014.06.006

Epidermal growth factor receptor and variant III targeted immunotherapy.

Immunotherapeutic approaches to cancer have shown remarkable promise. A critical barrier to successfully executing such immune-mediated interventions is the selection of safe yet immunogenic targets. As patient deaths have occurred when tumor-associated antigens shared by normal tissue have been targeted by strong cellular immunotherapeutic platforms, route of delivery, target selection and the immune-mediated approach undertaken must work together to maximize efficacy with safety. Selected tumor-specific targets can spare potential toxicity to normal tissue; however, they are far less common than tumor-associated antigens and may not be present on all patients. In the context of immunotherapy for high-grade glioma, 2 of the most prominently studied antigens are the tumor-associated epidermal growth factor receptor and its tumor-specific genetic deletion variant III. In this review, we will summarize the immune-mediated strategies employed against these targets as well as the caveats particular to these approaches.

Authors
Congdon, KL; Gedeon, PC; Suryadevara, CM; Caruso, HG; Cooper, LJN; Heimberger, AB; Sampson, JH
MLA Citation
Congdon, KL, Gedeon, PC, Suryadevara, CM, Caruso, HG, Cooper, LJN, Heimberger, AB, and Sampson, JH. "Epidermal growth factor receptor and variant III targeted immunotherapy." Neuro-oncology 16 Suppl 8 (October 2014): viii20-viii25. (Review)
PMID
25342601
Source
epmc
Published In
Neuro-Oncology
Volume
16 Suppl 8
Publish Date
2014
Start Page
viii20
End Page
viii25
DOI
10.1093/neuonc/nou236

A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma.

Robust methodology that allows objective, automated, and observer-independent measurements of brain tumor volume, especially after resection, is lacking. Thus, determination of tumor response and progression in neurooncology is unreliable. The objective of this study was to determine if a semi-automated volumetric method for quantifying enhancing tissue would perform with high reproducibility and low interobserver variability.Fifty-seven MR images from 13 patients with glioblastoma were assessed using our method, by 2 neuroradiologists, 1 neurosurgeon, 1 neurosurgical resident, 1 nurse practitioner, and 1 medical student. The 2 neuroradiologists also performed traditional 1-dimensional (1D) and 2-dimensional (2D) measurements. Intraclass correlation coefficients (ICCs) assessed interobserver variability between measurements. Radiological response was determined using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines and Macdonald criteria. Kappa statistics described interobserver variability of volumetric radiological response determinations.There was strong agreement for 1D (RECIST) and 2D (Macdonald) measurements between neuroradiologists (ICC = 0.42 and 0.61, respectively), but the agreement using the authors' novel automated approach was significantly stronger (ICC = 0.97). The volumetric method had the strongest agreement with regard to radiological response (κ = 0.96) when compared with 2D (κ = 0.54) or 1D (κ = 0.46) methods. Despite diverse levels of experience of the users of the volumetric method, measurements using the volumetric program remained remarkably consistent in all users (0.94).Interobserver variability using this new semi-automated method is less than the variability with traditional methods of tumor measurement. This new method is objective, quick, and highly reproducible among operators with varying levels of expertise. This approach should be further evaluated as a potential standard for response assessment based on contrast enhancement in brain tumors.

Authors
Kanaly, CW; Mehta, AI; Ding, D; Hoang, JK; Kranz, PG; Herndon, JE; Coan, A; Crocker, I; Waller, AF; Friedman, AH; Reardon, DA; Sampson, JH
MLA Citation
Kanaly, CW, Mehta, AI, Ding, D, Hoang, JK, Kranz, PG, Herndon, JE, Coan, A, Crocker, I, Waller, AF, Friedman, AH, Reardon, DA, and Sampson, JH. "A novel, reproducible, and objective method for volumetric magnetic resonance imaging assessment of enhancing glioblastoma." Journal of neurosurgery 121.3 (September 2014): 536-542.
PMID
25036205
Source
epmc
Published In
Journal of neurosurgery
Volume
121
Issue
3
Publish Date
2014
Start Page
536
End Page
542
DOI
10.3171/2014.4.jns121952

Worse outcomes for patients undergoing brain tumor and cerebrovascular procedures following the ACGME resident duty-hour restrictions.

On July 1, 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions for resident physicians due to concerns for patient and resident safety. Though duty-hour restrictions have increased resident quality of life, studies have shown mixed results with respect to patient outcomes. In this study, the authors have evaluated the effect of duty-hour restrictions on morbidity, mortality, length of stay, and charges in patients who underwent brain tumor and cerebrovascular procedures.The Nationwide Inpatient Sample was used to evaluate the effect of duty-hour restrictions on complications, mortality, length of stay, and charges by comparing the pre-reform (2000-2002) and post-reform (2005-2008) periods. Outcomes were compared between nonteaching and teaching hospitals using a difference-in-differences (DID) method.A total of 90,648 patients were included in the analysis. The overall complication rate was 11.7%, with the rates not significantly differing between the pre- and post-duty hour eras (p = 0.26). Examination of hospital teaching status revealed that complication rates decreased in nonteaching hospitals (12.1% vs 10.4%, p = 0.0004) and remained stable in teaching institutions (11.8% vs 11.9%, p = 0.73) in the post-reform era. Multivariate analysis demonstrated a significantly higher complication risk in teaching institutions (OR 1.33 [95% CI 1.11-1.59], p = 0.0022), with no significant change in nonteaching hospitals (OR 1.11 [95% CI 0.91-1.37], p = 0.31). A DID analysis to compare the magnitude in change between teaching and nonteaching institutions revealed that teaching hospitals had a significantly greater increase in complications during the post-reform era than nonteaching hospitals (p = 0.040). The overall mortality rate was 3.0%, with a significant decrease occurring in the post-reform era in both nonteaching (5.0% vs 3.2%, p < 0.0001) and teaching (3.2% vs 2.3%, p < 0.0001) hospitals. DID analysis to compare the changes in mortality between groups did not reveal a significant difference (p = 0.40). The mean length of stay for all patients was 8.7 days, with hospital stay decreasing from 9.2 days to 8.3 days in the post-reform era (p < 0.0001). The DID analysis revealed a greater length of stay decrease in nonteaching hospitals than teaching institutions, which approached significance (p = 0.055). Patient charges significantly increased in the post-reform era for all patients, increasing from $70,900 to $96,100 (p < 0.0001). The DID analysis did not reveal a significant difference between the changes in charges between teaching and nonteaching hospitals (p = 0.17).The implementation of duty-hour restrictions correlated with an increased risk of postoperative complications for patients undergoing brain tumor and cerebrovascular neurosurgical procedures. Duty-hour reform may therefore be associated with worse patient outcomes, contrary to its intended purpose. Due to the critical condition of many neurosurgical patients, this patient population is most sensitive and likely to be negatively affected by proposed future increased restrictions.

Authors
Babu, R; Thomas, S; Hazzard, MA; Friedman, AH; Sampson, JH; Adamson, C; Zomorodi, AR; Haglund, MM; Patil, CG; Boakye, M; Lad, SP
MLA Citation
Babu, R, Thomas, S, Hazzard, MA, Friedman, AH, Sampson, JH, Adamson, C, Zomorodi, AR, Haglund, MM, Patil, CG, Boakye, M, and Lad, SP. "Worse outcomes for patients undergoing brain tumor and cerebrovascular procedures following the ACGME resident duty-hour restrictions." Journal of neurosurgery 121.2 (August 2014): 262-276.
PMID
24926647
Source
epmc
Published In
Journal of neurosurgery
Volume
121
Issue
2
Publish Date
2014
Start Page
262
End Page
276
DOI
10.3171/2014.5.jns1314

Antibody-based immunotherapy for malignant glioma.

Conventional therapy for malignant glioma (MG) fails to specifically eliminate tumor cells, resulting in toxicity that limits therapeutic efficacy. In contrast, antibody-based immunotherapy uses the immune system to eliminate tumor cells with exquisite specificity. Increased understanding of the pathobiology of MG and the profound immunosuppression present among patients with MG has revealed several biologic targets amenable to antibody-based immunotherapy. Novel antibody engineering techniques allow for the production of fully human antibodies or antibody fragments with vastly reduced antigen-binding dissociation constants, increasing safety when used clinically as therapeutics. In this report, we summarize the use of antibody-based immunotherapy for MG. Approaches currently under investigation include the use of antibodies or antibody fragments to: (1) redirect immune effector cells to target tumor mutations, (2) inhibit immunosuppressive signals and thereby stimulate an immunological response against tumor cells, and (3) provide costimulatory signals to evoke immunologic targeting of tumor cells. These approaches demonstrate highly compelling safety and efficacy for the treatment of MG, providing a viable adjunct to current standard-of-care therapy for MG.

Authors
Gedeon, PC; Riccione, KA; Fecci, PE; Sampson, JH
MLA Citation
Gedeon, PC, Riccione, KA, Fecci, PE, and Sampson, JH. "Antibody-based immunotherapy for malignant glioma." Seminars in oncology 41.4 (August 2014): 496-510. (Review)
PMID
25173142
Source
epmc
Published In
Seminars in Oncology
Volume
41
Issue
4
Publish Date
2014
Start Page
496
End Page
510
DOI
10.1053/j.seminoncol.2014.06.004

Idh1 mutations as a immunotherapeutic target for brain tumors.

Immunotherapy promises an exquisitely precise therapeutic approach, and substantial evidence suggests that activated T cells can eradicate large tumors, even within the "immunologically privileged" brain. EGFRvIII and isocitrate dehydrogenase 1 (IDH1) mutations are two of the only consistent tumor-specific mutations that have been described. IDH1 is an evolutionarily-conserved enzyme essential to cell function. Greater than 90% of all IDH1 mutations occur from a substitution of histidine for arginine at codon 132, resulting in the highly conserved and tumor-specific mutation, IDH1R132H. IDH1R132H is homogeneously expressed in all tumor cells in tumors that express this mutation, including single infiltrating tumor cells but is absent in normal cells. The high frequency, specificity, and homogeneous expression of the IDH1 mutation make it an ideal target for therapeutic intervention.

Authors
Archer, GE; Reap, E; Norberg, P; Cui, X; Schmittling, R; Herndon, J; Chandramohan, V; Riccione, K; Kuan, CT; Yan, H; Bigner, DD; Sampson, JH
MLA Citation
Archer, GE, Reap, E, Norberg, P, Cui, X, Schmittling, R, Herndon, J, Chandramohan, V, Riccione, K, Kuan, CT, Yan, H, Bigner, DD, and Sampson, JH. "Idh1 mutations as a immunotherapeutic target for brain tumors." Neuro Oncol 16 Suppl 3 (July 2014): iii40-.
PMID
25165322
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii40
DOI
10.1093/neuonc/nou208.65

Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration.

PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. Within, we report on the ongoing phase I study evaluating the intratumoral convection-enhanced delivery (CED) of PVSRIPO.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration." Neuro Oncol 16 Suppl 3 (July 2014): iii43-.
PMID
25165331
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii43
DOI
10.1093/neuonc/nou209.5

Patient-derived xenografts mirror the proteomic profile of human glioblastoma: implications for personalized drug development.

(blind field).

Authors
Kwatra, MM; Brown, KE; Chagoya, G; Keir, ST; Bigner, DD; Sampson, JH
MLA Citation
Kwatra, MM, Brown, KE, Chagoya, G, Keir, ST, Bigner, DD, and Sampson, JH. "Patient-derived xenografts mirror the proteomic profile of human glioblastoma: implications for personalized drug development." Neuro Oncol 16 Suppl 3 (July 2014): iii38-.
PMID
25165310
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii38
DOI
10.1093/neuonc/nou208.57

Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM)

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Watts, J; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Watts, J, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM).

Authors
Sampson, JH; Viahovic, G; Desjardins, A; Friedman, HS; Baehring, JM; Hafler, D; Rollin, L; Coric, V; Perez, SN; Reardon, DA
MLA Citation
Sampson, JH, Viahovic, G, Desjardins, A, Friedman, HS, Baehring, JM, Hafler, D, Rollin, L, Coric, V, Perez, SN, and Reardon, DA. "Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells.

Despite aggressive conventional therapy, glioblastoma (GBM) remains uniformly lethal. Immunotherapy, in which the immune system is harnessed to specifically attack malignant cells, offers a treatment option with less toxicity. The expression of cytomegalovirus (CMV) antigens in GBM presents a unique opportunity to target these viral proteins for tumor immunotherapy. Although the presence of CMV within malignant gliomas has been confirmed by several laboratories, its relevance as an immunologic target in GBM has yet to be established. The objective of this study was to explore whether T cells stimulated by CMV pp65 RNA-transfected dendritic cells (DC) target and eliminate autologous GBM tumor cells in an antigen-specific manner.T cells from patients with GBM were stimulated with autologous DCs pulsed with CMV pp65 RNA, and the function of the effector CMV pp65-specific T cells was measured.In this study, we demonstrate the ability to elicit CMV pp65-specific immune responses in vitro using RNA-pulsed autologous DCs generated from patients with newly diagnosed GBM. Importantly, CMV pp65-specific T cells lyse autologous, primary GBM tumor cells in an antigen-specific manner. Moreover, T cells expanded in vitro using DCs pulsed with total tumor RNA demonstrated a 10- to 20-fold expansion of CMV pp65-specific T cells as assessed by tetramer analysis and recognition and killing of CMV pp65-expressing target cells.These data collectively demonstrate that CMV-specific T cells can effectively target glioblastoma tumor cells for immunologic killing and support the rationale for the development of CMV-directed immunotherapy in patients with GBM.

Authors
Nair, SK; De Leon, G; Boczkowski, D; Schmittling, R; Xie, W; Staats, J; Liu, R; Johnson, LA; Weinhold, K; Archer, GE; Sampson, JH; Mitchell, DA
MLA Citation
Nair, SK, De Leon, G, Boczkowski, D, Schmittling, R, Xie, W, Staats, J, Liu, R, Johnson, LA, Weinhold, K, Archer, GE, Sampson, JH, and Mitchell, DA. "Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells." Clinical cancer research : an official journal of the American Association for Cancer Research 20.10 (May 2014): 2684-2694.
PMID
24658154
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
10
Publish Date
2014
Start Page
2684
End Page
2694
DOI
10.1158/1078-0432.ccr-13-3268

Methodology and reporting of meta-analyses in the neurosurgical literature.

Authors
Sampson, JH; Barker, FG
MLA Citation
Sampson, JH, and Barker, FG. "Methodology and reporting of meta-analyses in the neurosurgical literature." Journal of neurosurgery 120.4 (April 2014): 791-794.
PMID
24460491
Source
epmc
Published In
Journal of neurosurgery
Volume
120
Issue
4
Publish Date
2014
Start Page
791
End Page
794
DOI
10.3171/2013.10.jns13724

Impact of PhD training on scholarship in a neurosurgical career.

OBJECT: The purpose of this study was to report the prevalence of neurosurgeons with both medical degrees (MDs) and doctorates (PhDs) at top-ranked US academic institutions and to assess whether the additional doctorate education is associated with substantive career involvement in academia as well as greater success in procuring National Institutes of Health (NIH) research funding compared with an MD-only degree. METHODS: The authors reviewed the training of neurosurgeons across the top 10 neurosurgery departments chosen according to academic impact (h index) to examine whether MD-PhD training correlated significantly with career outcomes in academia. RESULTS: Six hundred thirteen neurosurgery graduates and residents between the years 1990 and 2012 were identified for inclusion in this analysis. Both MD and PhD degrees were held by 121 neurosurgeons (19.7%), and an MD alone was held by 492. Over the past 2 decades, MD-PhD trainees represented a gradually increasing percentage of neurosurgeons, from 10.2% to 25.7% (p < 0.01). Of the neurosurgeons with MD-PhD training, a greater proportion had appointments in academic medicine compared with their MD-only peers (73.7% vs 52.3%, p < 0.001). Academic neurosurgeons with both degrees were also more likely to have received NIH funding (51.9% vs 31.8%, p < 0.05) than their single-degree counterparts in academia. In a national analysis of all active NIH R01 grants awarded in neurosurgery, MD-PhD investigators held a disproportionate number, more than 4-fold greater than their representation in the field. CONCLUSIONS: Dual MD-PhD training is a significant factor that may predict active participation in and funding for research careers among neurological surgeons at top-ranked academic institutions. These findings and their implications are of increasing relevance as the population of neurosurgeons with dual-degree training continues to rise.

Authors
Choi, BD; DeLong, MR; DeLong, DM; Friedman, AH; Sampson, JH
MLA Citation
Choi, BD, DeLong, MR, DeLong, DM, Friedman, AH, and Sampson, JH. "Impact of PhD training on scholarship in a neurosurgical career." J Neurosurg 120.3 (March 2014): 730-735.
PMID
24359004
Source
pubmed
Published In
Journal of neurosurgery
Volume
120
Issue
3
Publish Date
2014
Start Page
730
End Page
735
DOI
10.3171/2013.11.JNS122370

Response.

Authors
Choi, BD; DeLong, MR; Sampson, JH
MLA Citation
Choi, BD, DeLong, MR, and Sampson, JH. "Response." Journal of neurosurgery 120.3 (March 2014): 728-729.
PMID
24724172
Source
epmc
Published In
Journal of neurosurgery
Volume
120
Issue
3
Publish Date
2014
Start Page
728
End Page
729
DOI
10.3171/2013.11.jns122370

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss

Purpose: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. Experimental Design: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. Results: At elevated doses, infusion with EGFRvIIImCART cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIIINEG tumors, suggesting generation of host immunity against additional tumor antigens. Conclusion: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. © 2014 American Association for Cancer Research.

Authors
Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE; Kuan, CT; Morgan, RA; Rosenberg, SA; Johnson, LA
MLA Citation
Sampson, JH, Choi, BD, Sanchez-Perez, L, Suryadevara, CM, Snyder, DJ, Flores, CT, Schmittling, RJ, Nair, SK, Reap, EA, Norberg, PK, Herndon, JE, Kuan, CT, Morgan, RA, Rosenberg, SA, and Johnson, LA. "EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss." Clinical Cancer Research 20.4 (February 26, 2014): 972-984.
Source
scopus
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
4
Publish Date
2014
Start Page
972
End Page
984
DOI
10.1158/1078-0432.CCR-13-0709

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

PURPOSE: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. EXPERIMENTAL DESIGN: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. RESULTS: At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. CONCLUSION: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.

Authors
Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE; Kuan, C-T; Morgan, RA; Rosenberg, SA; Johnson, LA
MLA Citation
Sampson, JH, Choi, BD, Sanchez-Perez, L, Suryadevara, CM, Snyder, DJ, Flores, CT, Schmittling, RJ, Nair, SK, Reap, EA, Norberg, PK, Herndon, JE, Kuan, C-T, Morgan, RA, Rosenberg, SA, and Johnson, LA. "EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss." Clin Cancer Res 20.4 (February 15, 2014): 972-984.
PMID
24352643
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
4
Publish Date
2014
Start Page
972
End Page
984
DOI
10.1158/1078-0432.CCR-13-0709

SEER insights

Authors
Sampson, JH; Lad, SP; Herndon, JE; Starke, RM; Kondziolka, D
MLA Citation
Sampson, JH, Lad, SP, Herndon, JE, Starke, RM, and Kondziolka, D. "SEER insights." Journal of Neurosurgery 120.2 (February 1, 2014): 297-298.
Source
scopus
Published In
Journal of neurosurgery
Volume
120
Issue
2
Publish Date
2014
Start Page
297
End Page
298
DOI
10.3171/2013.6.JNS13993

SEER insights.

Authors
Sampson, JH; Lad, SP; Herndon, JE; Starke, RM; Kondziolka, D
MLA Citation
Sampson, JH, Lad, SP, Herndon, JE, Starke, RM, and Kondziolka, D. "SEER insights." J Neurosurg 120.2 (February 2014): 297-298.
PMID
24286150
Source
pubmed
Published In
Journal of neurosurgery
Volume
120
Issue
2
Publish Date
2014
Start Page
297
End Page
298
DOI
10.3171/2013.6.JNS13993

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. © 2013 Elsevier Ltd. All rights reserved.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." Journal of Clinical Neuroscience 21.1 (January 1, 2014): 189-190.
Source
scopus
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

Methodology and reporting of meta-analyses in the neurosurgical literature

Authors
Sampson, JH; Barker, FG
MLA Citation
Sampson, JH, and Barker, FG. "Methodology and reporting of meta-analyses in the neurosurgical literature." Journal of Neurosurgery 120.4 (January 1, 2014): 791-794.
Source
scopus
Published In
Journal of neurosurgery
Volume
120
Issue
4
Publish Date
2014
Start Page
791
End Page
794
DOI
10.3171/2013.10.JNS13724

Impact of PhD training on scholarship in a neurosurgical career: Clinical article

Object. The purpose of this study was to report the prevalence of neurosurgeons with both medical degrees (MDs) and doctorates (PhDs) at top-ranked US academic institutions and to assess whether the additional doctorate education is associated with substantive career involvement in academia as well as greater success in procuring National Institutes of Health (NIH) research funding compared with an MD-only degree. Methods. The authors reviewed the training of neurosurgeons across the top 10 neurosurgery departments chosen according to academic impact (h index) to examine whether MD-PhD training correlated significantly with career outcomes in academia. Results. Six hundred thirteen neurosurgery graduates and residents between the years 1990 and 2012 were identified for inclusion in this analysis. Both MD and PhD degrees were held by 121 neurosurgeons (19.7%), and an MD alone was held by 492. Over the past 2 decades, MD-PhD trainees represented a gradually increasing percentage of neurosurgeons, from 10.2% to 25.7% (p < 0.01). Of the neurosurgeons with MD-PhD training, a greater proportion had appointments in academic medicine compared with their MD-only peers (73.7% vs 52.3%, p < 0.001). Academic neurosurgeons with both degrees were also more likely to have received NIH funding (51.9% vs 31.8%, p < 0.05) than their single-degree counterparts in academia. In a national analysis of all active NIH R01 grants awarded in neurosurgery, MD-PhD investigators held a disproportionate number, more than 4-fold greater than their representation in the field. Conclusions. Dual MD-PhD training is a significant factor that may predict active participation in and funding for research careers among neurological surgeons at top-ranked academic institutions. These findings and their implications are of increasing relevance as the population of neurosurgeons with dual-degree training continues to rise. ©AANS, 2014.

Authors
Choi, BD; DeLong, MR; DeLong, DM; Friedman, AH; Sampson, JH
MLA Citation
Choi, BD, DeLong, MR, DeLong, DM, Friedman, AH, and Sampson, JH. "Impact of PhD training on scholarship in a neurosurgical career: Clinical article." Journal of Neurosurgery 120.3 (January 1, 2014): 730-735.
Source
scopus
Published In
Journal of neurosurgery
Volume
120
Issue
3
Publish Date
2014
Start Page
730
End Page
735
DOI
10.3171/2013.11.JNS122370

Oncolytic polio virotherapy of cancer

© 2014 American Cancer Society.Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (January 1, 2014): 3277-3286. (Review)
Source
scopus
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Editorial on "heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial".

Authors
Sampson, JH; Vlahovic, G
MLA Citation
Sampson, JH, and Vlahovic, G. "Editorial on "heat shock protein peptide complex-96 (HSPPC-96) vaccination for recurrent glioblastoma: a phase II, single arm trial"." Neuro-oncology 16.2 (January 2014): 169-170.
PMID
24443362
Source
epmc
Published In
Neuro-Oncology
Volume
16
Issue
2
Publish Date
2014
Start Page
169
End Page
170
DOI
10.1093/neuonc/not311

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

Authors
Miao, H; Choi, BD; Suryadevara, CM; Sanchez-Perez, L; Yang, S; De Leon, G; Sayour, EJ; McLendon, R; Herndon, JE; Healy, P; Archer, GE; Bigner, DD; Johnson, LA; Sampson, JH
MLA Citation
Miao, H, Choi, BD, Suryadevara, CM, Sanchez-Perez, L, Yang, S, De Leon, G, Sayour, EJ, McLendon, R, Herndon, JE, Healy, P, Archer, GE, Bigner, DD, Johnson, LA, and Sampson, JH. "EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma." PloS one 9.4 (January 2014): e94281-.
PMID
24722266
Source
epmc
Published In
PloS one
Volume
9
Issue
4
Publish Date
2014
Start Page
e94281
DOI
10.1371/journal.pone.0094281

Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and aggressive glial cell-derived primary tumor. Current standard of care for patients with GBM includes maximal tumor resection plus adjuvant radiotherapy and temozolomide chemotherapy, increasing median overall survival to a mere 15 months from diagnosis. Because these therapies are inherently nonspecific, there is an increased likelihood of off-target and incomplete effects; therefore, targeted modalities are required for enhanced safety and efficacy. Rindopepimut is emerging as a safe and potentially effective drug for the treatment of GBM. Rindopepimut consists of a 14-mer peptide that spans the length of EGF receptor variant III, a mutant variant of EGF receptor found on approximately 30% of primary GBM, conjugated to the carrier protein keyhole limpet hemocyanin. Vaccination with rindopepimut has been shown to specifically eliminate cells expressing EGF receptor variant III. Phase II clinical trials have suggested that vaccination of newly diagnosed GBM patients with rindopepimut plus adjuvant granulocyte-macrophage colony-stimulating factor results in prolonged progression-free and overall survival with minimal toxicity. This review will outline the development of rindopepimut, as well as the current status of this vaccine.

Authors
Swartz, AM; Li, Q-J; Sampson, JH
MLA Citation
Swartz, AM, Li, Q-J, and Sampson, JH. "Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme." Immunotherapy 6.6 (January 2014): 679-690. (Review)
PMID
25186601
Source
epmc
Published In
Immunotherapy
Volume
6
Issue
6
Publish Date
2014
Start Page
679
End Page
690
DOI
10.2217/imt.14.21

Immunological targeting of cytomegalovirus for glioblastoma therapy.

Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM.

Authors
Nair, SK; Sampson, JH; Mitchell, DA
MLA Citation
Nair, SK, Sampson, JH, and Mitchell, DA. "Immunological targeting of cytomegalovirus for glioblastoma therapy." Oncoimmunology 3 (January 2014): e29289-.
PMID
25101224
Source
epmc
Published In
OncoImmunology
Volume
3
Publish Date
2014
Start Page
e29289
DOI
10.4161/onci.29289

Leveraging chemotherapy-induced lymphopenia to potentiate cancer immunotherapy.

First-line chemotherapy to combat primary malignant brain cancer is often accompanied by lymphopenic immunologic deficiency. Although counterintuitive, chemotherapy-induced lymphopenia can provide excellent host conditioning that may actually be leveraged to potentiate antitumor immunotherapy. We discuss here our preclinical and clinical experiences applying immunotherapy against glioblastoma, the most common and lethal primary malignant brain tumor, as well as the use of immunotherapeutics in the setting of standard-of-care temozolomide chemotherapy.

Authors
Sanchez-Perez, L; Suryadevara, CM; Choi, BD; Reap, EA; Sampson, JH
MLA Citation
Sanchez-Perez, L, Suryadevara, CM, Choi, BD, Reap, EA, and Sampson, JH. "Leveraging chemotherapy-induced lymphopenia to potentiate cancer immunotherapy." Oncoimmunology 3.7 (January 2014): e944054-.
PMID
25610727
Source
epmc
Published In
OncoImmunology
Volume
3
Issue
7
Publish Date
2014
Start Page
e944054
DOI
10.4161/21624011.2014.944054

Chimeric antigen receptor engineered T cells can eliminate brain tumors and initiate long-term protection against recurrence.

CAR therapy has shown promise in treating cancer, but at the cost of unexpected toxicity against normal tissues, not predicted by preclinical testing. We are working to generate more physiologically relevant models for preclinical CAR toxicity testing, and in doing so, have discovered that CAR therapy induces immunogenic cell death, with the potential for cures.

Authors
Johnson, LA; Sanchez-Perez, L; Suryadevara, CM; Sampson, JH
MLA Citation
Johnson, LA, Sanchez-Perez, L, Suryadevara, CM, and Sampson, JH. "Chimeric antigen receptor engineered T cells can eliminate brain tumors and initiate long-term protection against recurrence." Oncoimmunology 3.7 (January 2014): e944059-.
PMID
25610729
Source
epmc
Published In
OncoImmunology
Volume
3
Issue
7
Publish Date
2014
Start Page
e944059
DOI
10.4161/21624011.2014.944059

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma.

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." J Clin Neurosci 21.1 (January 2014): 189-190.
PMID
24054399
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway. © 2013 Landes Bioscience.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody." OncoImmunology 2.12 (December 1, 2013): 1-2.
Source
scopus
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
1
End Page
2
DOI
10.4161/onci.26757

Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody.

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody." Oncoimmunology 2.12 (December 2013): e26757-.
PMID
24475376
Source
epmc
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
e26757
DOI
10.4161/onci.26757

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model

Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Yang, S; Archer, GE; Flores, CE; Mitchell, DA; Sampson, JH
MLA Citation
Yang, S, Archer, GE, Flores, CE, Mitchell, DA, and Sampson, JH. "A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model." Cancer Immunology, Immunotherapy 62.11 (November 1, 2013): 1649-1662.
Source
scopus
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
11
Publish Date
2013
Start Page
1649
End Page
1662
DOI
10.1007/s00262-013-1464-0

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model.

Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.

Authors
Yang, S; Archer, GE; Flores, CE; Mitchell, DA; Sampson, JH
MLA Citation
Yang, S, Archer, GE, Flores, CE, Mitchell, DA, and Sampson, JH. "A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model." Cancer Immunol Immunother 62.11 (November 2013): 1649-1662.
PMID
23982483
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
11
Publish Date
2013
Start Page
1649
End Page
1662
DOI
10.1007/s00262-013-1464-0

Enhanced oncolytic virotherapy through oxidative stress inhibition.

Authors
Congdon, KL; Sampson, JH
MLA Citation
Congdon, KL, and Sampson, JH. "Enhanced oncolytic virotherapy through oxidative stress inhibition." Mol Ther 21.11 (November 2013): 1981-1983.
PMID
24201213
Source
pubmed
Published In
Molecular Therapy
Volume
21
Issue
11
Publish Date
2013
Start Page
1981
End Page
1983
DOI
10.1038/mt.2013.227

Complete response to steroids in dural inflammatory pseudotumor associated with Still's disease.

We report a unique case of a dural-based inflammatory pseudotumor (IPT) arising in the left cavernous sinus of a patient with a history of juvenile Still's disease. The patient presented with hemi-facial paresthesias, dull, constant headaches, and transient episodes of sharp pain along the temporalis region. Treatment with oral steroid therapy resulted in complete regression of the lesion and accompanied neuralgia symptoms. Because intracranial IPT can mimic meningiomas both clinically and radiographically and can be associated with systemic arthritic diseases, neurosurgeons should be familiar with this entity in order to avoid unnecessary radical surgery and alternatively consider a tapering course of steroid therapy.

Authors
Batich, KA; William St Clair, E; McLendon, RE; Sampson, JH
MLA Citation
Batich, KA, William St Clair, E, McLendon, RE, and Sampson, JH. "Complete response to steroids in dural inflammatory pseudotumor associated with Still's disease." J Clin Neurosci 20.10 (October 2013): 1445-1448.
PMID
23768965
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
20
Issue
10
Publish Date
2013
Start Page
1445
End Page
1448
DOI
10.1016/j.jocn.2013.01.009

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis.

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms.

Authors
Choi, BD; Gedeon, PC; Kuan, C-T; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, C-T, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." J Immunol Methods 395.1-2 (September 30, 2013): 14-20.
PMID
23806556
Source
pubmed
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET)

Authors
Gururangan, S; Grant, GA; Driscoll, T; Archer, G; Sayour, EJ; II, HJE; Friedman, HS; Kurtzberg, J; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Gururangan, S, Grant, GA, Driscoll, T, Archer, G, Sayour, EJ, II, HJE, Friedman, HS, Kurtzberg, J, Bigner, DD, Sampson, JH, and Mitchell, DA. "ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET)." PEDIATRIC BLOOD & CANCER 60 (September 2013): 13-13.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
13
End Page
13

Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody.

A major mechanism by which human regulatory T cells (T(regs)) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether T(regs) also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAbs) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted TCR recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T(regs) to kill glioblastoma (GBM) cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary GBM also displayed diffuse infiltration of granzyme-expressing FoxP3(+) T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating T(regs) possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis.

Authors
Choi, BD; Gedeon, PC; Herndon, JE; Archer, GE; Reap, EA; Sanchez-Perez, L; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Herndon, JE, Archer, GE, Reap, EA, Sanchez-Perez, L, Mitchell, DA, Bigner, DD, and Sampson, JH. "Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody." Cancer immunology research 1.3 (September 2013): 163-.
PMID
24570975
Source
epmc
Published In
Cancer Immunology Research
Volume
1
Issue
3
Publish Date
2013
Start Page
163
DOI
10.1158/2326-6066.cir-13-0049

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial.

PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach.

Authors
Cabrera, AR; Cuneo, KC; Desjardins, A; Sampson, JH; McSherry, F; Herndon, JE; Peters, KB; Allen, K; Hoang, JK; Chang, Z; Craciunescu, O; Vredenburgh, JJ; Friedman, HS; Kirkpatrick, JP
MLA Citation
Cabrera, AR, Cuneo, KC, Desjardins, A, Sampson, JH, McSherry, F, Herndon, JE, Peters, KB, Allen, K, Hoang, JK, Chang, Z, Craciunescu, O, Vredenburgh, JJ, Friedman, HS, and Kirkpatrick, JP. "Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial." Int J Radiat Oncol Biol Phys 86.5 (August 1, 2013): 873-879.
PMID
23725997
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
86
Issue
5
Publish Date
2013
Start Page
873
End Page
879
DOI
10.1016/j.ijrobp.2013.04.029

Dose-Finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent Glioblastoma

Authors
Sampson, JH; Desjardins, A; Peters, KB; Ranjan, T; Vlahovic, G; Lally-Goss, D; Threatt, S; Herndon, J; Friedman, AH; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Sampson, JH, Desjardins, A, Peters, KB, Ranjan, T, Vlahovic, G, Lally-Goss, D, Threatt, S, Herndon, J, Friedman, AH, Friedman, H, Bigner, D, and Gromeier, M. "Dose-Finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent Glioblastoma." August 2013.
Source
wos-lite
Published In
Neurosurgery
Volume
60
Publish Date
2013
Start Page
155
End Page
155

Clinicopathological characteristics and treatment of rhabdoid glioblastoma Clinical article

Authors
Babu, R; Hatef, J; McLendon, RE; Cummings, TJ; Sampson, JH; Friedman, AH; Adamson, C
MLA Citation
Babu, R, Hatef, J, McLendon, RE, Cummings, TJ, Sampson, JH, Friedman, AH, and Adamson, C. "Clinicopathological characteristics and treatment of rhabdoid glioblastoma Clinical article." JOURNAL OF NEUROSURGERY 119.2 (August 2013): 412-419.
PMID
23641829
Source
wos-lite
Published In
Journal of neurosurgery
Volume
119
Issue
2
Publish Date
2013
Start Page
412
End Page
419
DOI
10.3171/2013.3.JNS121773

Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors.

Modest improvement in brain tumor patient survival has been achieved through advances in surgical, adjuvant radiation and chemotherapeutic strategies. However, these traditional approaches have been unsuccessful in permanently controlling these aggressive tumors, with recurrence being quite common. Hence, there is a need for novel therapeutic approaches that specifically target the molecularly diverse brain tumor cell population. The ability of the immune system to recognize altered tumor cells while avoiding surrounding normal cells offers an enormous advantage over the nonspecific nature of the conventional treatment schemes. Therefore, immunotherapy represents a promising approach that may supplement the standard therapies in eliminating the residual brain tumor cells. This review summarizes different immunotherapeutic approaches currently being tested for malignant brain tumor treatment.

Authors
Chandramohan, V; Mitchell, DA; Johnson, LA; Sampson, JH; Bigner, DD
MLA Citation
Chandramohan, V, Mitchell, DA, Johnson, LA, Sampson, JH, and Bigner, DD. "Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors." Future oncology (London, England) 9.7 (July 2013): 977-990. (Review)
PMID
23837761
Source
epmc
Published In
Future oncology (London, England)
Volume
9
Issue
7
Publish Date
2013
Start Page
977
End Page
990
DOI
10.2217/fon.13.47

An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma.

While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics.

Authors
Gedeon, PC; Choi, BD; Hodges, TR; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Gedeon, PC, Choi, BD, Hodges, TR, Mitchell, DA, Bigner, DD, and Sampson, JH. "An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma." Expert Rev Clin Pharmacol 6.4 (July 2013): 375-386. (Review)
PMID
23927666
Source
pubmed
Published In
Expert review of clinical pharmacology
Volume
6
Issue
4
Publish Date
2013
Start Page
375
End Page
386
DOI
10.1586/17512433.2013.811806

Contemporary surgical management of vestibular schwannomas: analysis of complications and lessons learned over the past decade.

BACKGROUND: Despite advanced microsurgical techniques, more refined instrumentation, and expert team management, there is still a significant incidence of complications in vestibular schwannoma surgery. OBJECTIVE: To analyze complications from the microsurgical treatment of vestibular schwannoma by an expert surgical team and to propose strategies for minimizing such complications. METHODS: Surgical outcomes and complications were evaluated in a consecutive series of 410 unilateral vestibular schwannomas treated from 2000 to 2009. Clinical status and complications were assessed postoperatively (within 7 days) and at the time of follow-up (range, 1-116 months; mean, 32.7 months). RESULTS: Follow-up data were available for 357 of the 410 patients (87.1%). Microsurgical tumor resection was performed through a retrosigmoid approach in 70.7% of cases. Thirty-three patients (8%) had intrameatal tumors and 204 (49.8%) had tumors that were <20 mm. Gross total resection was performed in 306 patients (74.6%). Hearing preservation surgery was attempted in 170 patients with tumors <20 mm, and good hearing was preserved in 74.1%. The main neurological complication was facial palsy (House-Brackmann grade III-VI), observed in 14% of patients (56 cases) postoperatively; however, 59% of them improved during the follow-up period. Other neurological complications were disequilibrium in 6.3%, facial numbness in 2.2%, and lower cranial nerve deficit in 0.5%. Nonneurological complications included cerebrospinal fluid leaks in 7.6%, wound infection in 2.2%, and meningitis in 1.7%. CONCLUSION: Many of these complications are avoidable through further refinement of operative technique, and strategies for avoiding complications are proposed.

Authors
Nonaka, Y; Fukushima, T; Watanabe, K; Friedman, AH; Sampson, JH; Mcelveen, JT; Cunningham, CD; Zomorodi, AR
MLA Citation
Nonaka, Y, Fukushima, T, Watanabe, K, Friedman, AH, Sampson, JH, Mcelveen, JT, Cunningham, CD, and Zomorodi, AR. "Contemporary surgical management of vestibular schwannomas: analysis of complications and lessons learned over the past decade." Neurosurgery 72.2 Suppl Operative (June 2013): ons103-ons115.
PMID
23037828
Source
pubmed
Published In
Neurosurgery
Volume
72
Issue
2 Suppl Operative
Publish Date
2013
Start Page
ons103
End Page
ons115
DOI
10.1227/NEU.0b013e3182752b05

Isocitrate dehydrogenase 1: what it means to the neurosurgeon: a review.

Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.

Authors
Hodges, TR; Choi, BD; Bigner, DD; Yan, H; Sampson, JH
MLA Citation
Hodges, TR, Choi, BD, Bigner, DD, Yan, H, and Sampson, JH. "Isocitrate dehydrogenase 1: what it means to the neurosurgeon: a review." J Neurosurg 118.6 (June 2013): 1176-1180. (Review)
PMID
23581583
Source
pubmed
Published In
Journal of neurosurgery
Volume
118
Issue
6
Publish Date
2013
Start Page
1176
End Page
1180
DOI
10.3171/2013.3.JNS122282

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide.

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; Herndon, JE; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, Herndon, JE, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunol Immunother 62.6 (June 2013): 983-987.
PMID
23591978
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT.

Authors
Ranjan, T; Peters, KB; Vlahovic, G; Alderson, LM; Herndon, JE; McSherry, F; Threatt, S; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ; Desjardins, A
MLA Citation
Ranjan, T, Peters, KB, Vlahovic, G, Alderson, LM, Herndon, JE, McSherry, F, Threatt, S, Sampson, JH, Friedman, AH, Bigner, DD, Friedman, HS, Vredenburgh, JJ, and Desjardins, A. "Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Current immunotherapeutic targets in gliomas

The prospect for high-grade astrocytic tumor patients continues to be dismal, evenwith advances in surgery, radiotherapy, and chemotherapy. There is a need for thedevelopment of novel therapies that would eliminate the heterogeneous and diffuseastrocytic tumor cells.Innovative therapeutic approaches for the treatment of central nervous systemneoplasia, such as antibody-mediated immunotherapeutics, cellular immunotherapeutics,and oncolytic viruses targeting tumor-associated antigens, have emerged during the pastfew years.Herein we review several of the glioma-associated antigens and the current status ofimmunotherapeutics and oncolytic viruses targeting these antigens. © 2013 Nova Science Publishers, Inc. All rights reserved.

Authors
Chandramohan, V; Mitchell, DA; Gromeier, M; Sampson, JH; Bigner, DD
MLA Citation
Chandramohan, V, Mitchell, DA, Gromeier, M, Sampson, JH, and Bigner, DD. "Current immunotherapeutic targets in gliomas." (May 1, 2013): 287-305. (Chapter)
Source
scopus
Publish Date
2013
Start Page
287
End Page
305

Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier.

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting.

Authors
Mehta, AI; Brufsky, AM; Sampson, JH
MLA Citation
Mehta, AI, Brufsky, AM, and Sampson, JH. "Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier." Cancer Treat Rev 39.3 (May 2013): 261-269. (Review)
PMID
22727691
Source
pubmed
Published In
Cancer Treatment Reviews
Volume
39
Issue
3
Publish Date
2013
Start Page
261
End Page
269
DOI
10.1016/j.ctrv.2012.05.006

A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system.

Bispecific T-cell engagers (BiTEs) may break multiple barriers that currently limit the use of immunotherapy in glioblastoma patients. We have recently described a novel BiTE specific for a mutated form of the epidermal growth factor receptor, EGFRvIII, that exerts potent antineoplastic effects against established invasive tumors of the brain.

Authors
Choi, BD; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Pastan, I, Bigner, DD, and Sampson, JH. "A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system." Oncoimmunology 2.4 (April 1, 2013): e23639-.
PMID
23734318
Source
pubmed
Published In
OncoImmunology
Volume
2
Issue
4
Publish Date
2013
Start Page
e23639
DOI
10.4161/onci.23639

ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS

Authors
Gromeier, M; Desjardins, A; Sampson, JH; Threatt, SJE; Herndon, JE; Friedman, A; Friedman, HS; Bigner, DD
MLA Citation
Gromeier, M, Desjardins, A, Sampson, JH, Threatt, SJE, Herndon, JE, Friedman, A, Friedman, HS, and Bigner, DD. "ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
20
End Page
20

DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES

Authors
Pham, CD; Pei, Y; Flores, C; Snyder, D; Bigner, DD; Sampson, JH; Wechsler-Reya, RJ; Mitchell, DA
MLA Citation
Pham, CD, Pei, Y, Flores, C, Snyder, D, Bigner, DD, Sampson, JH, Wechsler-Reya, RJ, and Mitchell, DA. "DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
42
End Page
43

Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic.

Glioblastoma, the most common primary malignant brain tumor, is among the most difficult cancers to treat. Despite the aggressive standard of care, including surgical removal followed by radiotherapy with concomitant and adjuvant chemotherapy, the often sudden onset, diffuse infiltrating nature and highly malignant features of the lesion result in a median overall survival of < 15 months. Currently employed standard- of-care therapy for glioblastoma is nonspecific, leading to premature withdrawal of treatment due to off-target toxicity. Rindopepimut is a peptide-based vaccine that elicits a potent humoral and cellular immune response specifically against cells expressing EGFRvIII, a rearranged, cell-surface tyrosine kinase receptor present exclusively in glioblastoma and other common neoplasms. Several phase I and phase II clinical trials have demonstrated that vaccination with rindopepimut is safe, well tolerated and produces a highly potent immune response that effectively eradicates EGFRvIII-expressing tumor cells, leading to a 73% increase in survival among patients with newly diagnosed glioblastoma. Furthermore, temozolomide-induced lymphopenia enhances the rindopepimut-induced immune response against EGFRvIII, allowing for enhanced vaccination responses in the context of standard-of-care chemotherapy. Rindopepimut is currently undergoing evaluation in a phase III international trial for newly diagnosed glioblastoma and is under clinical investigation for recurrent glioblastoma and pediatric brain stem gliomas.

Authors
Gedeon, PC; Choi, BD; Sampson, JH; Bigner, DD
MLA Citation
Gedeon, PC, Choi, BD, Sampson, JH, and Bigner, DD. "Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic." Drugs of the future 38.3 (March 2013): 147-155.
PMID
25663738
Source
epmc
Published In
Drugs of the future
Volume
38
Issue
3
Publish Date
2013
Start Page
147
End Page
155

RINDOPEPIMUT Anti-EGFRvIII Peptide Vaccine Oncolytic

Authors
Gedeon, PC; Choi, BD; Sampson, JH; Bigner, DD
MLA Citation
Gedeon, PC, Choi, BD, Sampson, JH, and Bigner, DD. "RINDOPEPIMUT Anti-EGFRvIII Peptide Vaccine Oncolytic." DRUGS OF THE FUTURE 38.3 (March 2013): 147-155.
Source
wos-lite
Published In
Drugs of the future
Volume
38
Issue
3
Publish Date
2013
Start Page
147
End Page
155
DOI
10.1358/dof.2013.038.03.1933992

Thickness of subcutaneous fat as a risk factor for infection in cervical spine fusion surgery.

Surgical site infections increase the incidence of morbidity and mortality as well as health-care expenses. The cost of care increases threefold to fourfold as a consequence of surgical site infection after spinal surgery. The aim of the present study was to determine the role of subcutaneous fat thickness in the development of surgical site infection following cervical spine fusion surgery.We performed a retrospective review of a consecutive cohort of 213 adult patients who underwent posterior cervical spine fusion between 2006 and 2008 at Duke University Medical Center. The horizontal distance from the lamina to the skin surface at the C5 level and the thickness of subcutaneous fat were measured, and the ratio of the fat thickness to the total distance at the surgical site was determined. Previously identified risk factors for the development of surgical site infection were also recorded.Twenty-two of the 213 patients developed a postoperative infection. Obesity (body mass index ≥ 30 kg/m2) was not a significant risk factor for surgical site infection; the body mass index (and 95% confidence interval) was 29.4 ± 1.2 kg/m2 in the patients who developed a surgical site infection compared with 28.9 ± 0.94 kg/m2 in the patients without an infection. However, the thickness of subcutaneous fat and the ratio of the fat thickness to the lamina-to-skin distance were both significant risk factors for infection. The thickness of subcutaneous fat was 27.0 ± 2.5 mm in the patients who developed a surgical site infection group compared with 21.4 ± 0.88 mm in the patients without an infection (p = 0.042). The ratio of fat thickness to total thickness was 0.42 ± 0.019 in the patients who developed a surgical site infection compared with 0.35 ± 0.01 in the patients without an infection (p = 0.020). Multivariate analysis revealed this ratio to be an independent risk factor for developing a postoperative infection (odds ratio, 3.18; 95% confidence interval, 1.02 to 9.97).The study demonstrated that the thickness of subcutaneous fat at the surgical site is a factor in the development of surgical site infection following cervical spine fusion and deserves assessment in the preoperative evaluation.

Authors
Mehta, AI; Babu, R; Sharma, R; Karikari, IO; Grunch, BH; Owens, TR; Agarwal, VJ; Sampson, JH; Lad, SP; Friedman, AH; Kuchibhatla, M; Bagley, CA; Gottfried, ON
MLA Citation
Mehta, AI, Babu, R, Sharma, R, Karikari, IO, Grunch, BH, Owens, TR, Agarwal, VJ, Sampson, JH, Lad, SP, Friedman, AH, Kuchibhatla, M, Bagley, CA, and Gottfried, ON. "Thickness of subcutaneous fat as a risk factor for infection in cervical spine fusion surgery." The Journal of bone and joint surgery. American volume 95.4 (February 2013): 323-328.
PMID
23426766
Source
epmc
Published In
The Journal of Bone and Joint Surgery
Volume
95
Issue
4
Publish Date
2013
Start Page
323
End Page
328
DOI
10.2106/jbjs.l.00225

Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma.

Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.

Authors
Choi, BD; Kuan, C-T; Cai, M; Archer, GE; Mitchell, DA; Gedeon, PC; Sanchez-Perez, L; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Kuan, C-T, Cai, M, Archer, GE, Mitchell, DA, Gedeon, PC, Sanchez-Perez, L, Pastan, I, Bigner, DD, and Sampson, JH. "Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma." Proc Natl Acad Sci U S A 110.1 (January 2, 2013): 270-275.
PMID
23248284
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
1
Publish Date
2013
Start Page
270
End Page
275
DOI
10.1073/pnas.1219817110

Subarachnoid hemorrhage trials

Authors
Zomorodi, A; II, HJE; Sampson, JH
MLA Citation
Zomorodi, A, II, HJE, and Sampson, JH. "Subarachnoid hemorrhage trials." NEUROSURGICAL FOCUS 34.1 (January 2013): 1-2.
Source
wos-lite
Published In
Neurosurgical focus
Volume
34
Issue
1
Publish Date
2013
Start Page
1
End Page
2
DOI
10.3171/2012.5.JNS12730

Subarachnoid hemorrhage trials

Authors
Zomorodi, A; II, HJE; Sampson, JH
MLA Citation
Zomorodi, A, II, HJE, and Sampson, JH. "Subarachnoid hemorrhage trials." JOURNAL OF NEUROSURGERY 118.1 (January 2013): 1-2.
PMID
23039153
Source
wos-lite
Published In
Journal of neurosurgery
Volume
118
Issue
1
Publish Date
2013
Start Page
1
End Page
2
DOI
10.3171/2012.5.JNS12730

Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice.

Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4(+), CD8(+) T-cell and CD4(+)Foxp3(+) TReg counts. Adoptive transfer of naïve CD8(+) T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8(+) T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ-but not lymphodepletive, NMA TMZ-led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.

Authors
Sanchez-Perez, LA; Choi, BD; Archer, GE; Cui, X; Flores, C; Johnson, LA; Schmittling, RJ; Snyder, D; Herndon, JE; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, LA, Choi, BD, Archer, GE, Cui, X, Flores, C, Johnson, LA, Schmittling, RJ, Snyder, D, Herndon, JE, Bigner, DD, Mitchell, DA, and Sampson, JH. "Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice." PLoS One 8.3 (2013): e59082-.
PMID
23527092
Source
pubmed
Published In
PloS one
Volume
8
Issue
3
Publish Date
2013
Start Page
e59082
DOI
10.1371/journal.pone.0059082

Therapeutic approaches for HER2-positive brain metastases: Circumventing the blood-brain barrier

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting. © 2012 Elsevier Ltd.

Authors
Mehta, AI; Brufsky, AM; Sampson, JH
MLA Citation
Mehta, AI, Brufsky, AM, and Sampson, JH. "Therapeutic approaches for HER2-positive brain metastases: Circumventing the blood-brain barrier." Cancer Treatment Reviews 39.3 (2013): 261-269.
Source
scival
Published In
Cancer Treatment Reviews
Volume
39
Issue
3
Publish Date
2013
Start Page
261
End Page
269
DOI
10.1016/j.ctrv.2012.05.006

Radiotherapy and Radiosurgery for Tumors of the Central Nervous System

In this article, the application of radiotherapy, alone and in combination with surgery and chemotherapy, in the treatment of metastases to the brain (the most common malignant brain lesion), primary malignant gliomas (the most common malignant primary brain tumor), and metastases to the osseous spine is reviewed. Brain metastases may be treated with surgical resection, whole-brain radiotherapy, stereotactic radiosurgery, or some combination of these treatments. The optimum treatment of brain metastases is a matter of controversy, and patient and disease factors favoring one treatment scheme over another are presented. © 2013 Elsevier Inc. All rights reserved.

Authors
Kirkpatrick, JP; Yin, F-F; Sampson, JH
MLA Citation
Kirkpatrick, JP, Yin, F-F, and Sampson, JH. "Radiotherapy and Radiosurgery for Tumors of the Central Nervous System." Surgical Oncology Clinics of North America (2013).
PMID
23622073
Source
scival
Published In
Surgical Oncology Clinics of North America
Publish Date
2013
DOI
10.1016/j.soc.2013.02.008

Radiotherapy and Radiosurgery for Tumors of the Central Nervous System

In this article, the application of radiotherapy, alone and in combination with surgery and chemotherapy, in the treatment of metastases to the brain (the most common malignant brain lesion), primary malignant gliomas (the most common malignant primary brain tumor), and metastases to the osseous spine is reviewed. Brain metastases may be treated with surgical resection, whole-brain radiotherapy, stereotactic radiosurgery, or some combination of these treatments. The optimum treatment of brain metastases is a matter of controversy, and patient and disease factors favoring one approach over another are presented. © 2013 Elsevier Inc.

Authors
Kirkpatrick, JP; Yin, FF; Sampson, JH
MLA Citation
Kirkpatrick, JP, Yin, FF, and Sampson, JH. "Radiotherapy and Radiosurgery for Tumors of the Central Nervous System." Surgical Oncology Clinics of North America 22.3 (2013): 445-461.
Source
scival
Published In
Surgical Oncology Clinics of North America
Volume
22
Issue
3
Publish Date
2013
Start Page
445
End Page
461
DOI
10.1016/j.soc.2013.02.008

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; II, JEH; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, II, JEH, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunology, Immunotherapy 62.6 (2013): 983-987.
Source
scival
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma

Outcome for glioblastoma (GBM), the most common primary CNS malignancy, remains poor. The overall survival benefit recently achieved with immunotherapeutics for melanoma and prostate cancer support evaluation of immunotherapies for other challenging cancers, including GBM. Much historical dogma depicting the CNS as immunoprivileged has been replaced by data demonstrating CNS immunocompetence and active interaction with the peripheral immune system. Several glioma antigens have been identified for potential immunotherapeutic exploitation. Active immunotherapy studies for GBM, supported by preclinical data, have focused on tumor lysate and synthetic antigen vaccination strategies. Results to date confirm consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed. These findings underscore the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors. Additional immunotherapy strategies are also in development for GBM. Future studies may consider combinatorial immunotherapy strategies with complimentary actions. © 2013 Expert Reviews Ltd.

Authors
Reardon, DA; Wucherpfennig, KW; Freeman, G; Wu, CJ; Chiocca, EA; Wen, PY; Curry, WT; Mitchell, DA; Fecci, PE; Sampson, JH; Dranoff, G
MLA Citation
Reardon, DA, Wucherpfennig, KW, Freeman, G, Wu, CJ, Chiocca, EA, Wen, PY, Curry, WT, Mitchell, DA, Fecci, PE, Sampson, JH, and Dranoff, G. "An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma." Expert Review of Vaccines 12.6 (2013): 597-615.
PMID
23750791
Source
scival
Published In
Expert Review of Vaccines
Volume
12
Issue
6
Publish Date
2013
Start Page
597
End Page
615
DOI
10.1586/erv.13.41

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo. Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5). Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2+ subjects, CD8+ T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion. These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs. Trial registration. Clinicaltrials.gov NCT00672542.

Authors
Dannull, J; Haley, NR; Archer, G; Nair, S; Boczkowski, D; Harper, M; Rosa, ND; Pickett, N; Mosca, PJ; Burchette, J; Selim, MA; Mitchell, DA; Sampson, J; Tyler, DS; Pruitt, SK
MLA Citation
Dannull, J, Haley, NR, Archer, G, Nair, S, Boczkowski, D, Harper, M, Rosa, ND, Pickett, N, Mosca, PJ, Burchette, J, Selim, MA, Mitchell, DA, Sampson, J, Tyler, DS, and Pruitt, SK. "Melanoma immunotherapy using mature DCs expressing the constitutive proteasome." Journal of Clinical Investigation 123.7 (2013): 3135-3145.
PMID
23934126
Source
scival
Published In
Journal of Clinical Investigation
Volume
123
Issue
7
Publish Date
2013
Start Page
3135
End Page
3145
DOI
10.1172/JCI67544

Contemporary surgical management of vestibular schwannomas: Analysis of complications and lessons learned over the past decade

BACKGROUND:: Despite advanced microsurgical techniques, more refined instrumentation, and expert team management, there is still a significant incidence of complications in vestibular schwannoma surgery. OBJECTIVE:: To analyze complications from the microsurgical treatment of vestibular schwannoma by an expert surgical team and to propose strategies for minimizing such complications. METHODS:: Surgical outcomes and complications were evaluated in a consecutive series of 410 unilateral vestibular schwannomas treated from 2000 to 2009. Clinical status and complications were assessed postoperatively (within 7 days) and at the time of follow-up (range, 1-116 months; mean, 32.7 months). RESULTS:: Follow-up data were available for 357 of the 410 patients (87.1%). Microsurgical tumor resection was performed through a retrosigmoid approach in 70.7% of cases. Thirty-three patients (8%) had intrameatal tumors and 204 (49.8%) had tumors that were <20 mm. Gross total resection was performed in 306 patients (74.6%). Hearing preservation surgery was attempted in 170 patients with tumors <20 mm, and good hearing was preserved in 74.1%. The main neurological complication was facial palsy (House-Brackmann grade III-VI), observed in 14% of patients (56 cases) postoperatively; however, 59% of them improved during the follow-up period. Other neurological complications were disequilibrium in 6.3%, facial numbness in 2.2%, and lower cranial nerve deficit in 0.5%. Nonneurological complications included cerebrospinal fluid leaks in 7.6%, wound infection in 2.2%, and meningitis in 1.7%. CONCLUSION:: Many of these complications are avoidable through further refinement of operative technique, and strategies for avoiding complications are proposed. ABBREVIATIONS:: ABR, auditory brainstem responseAICA, anterior inferior cerebellar arteryCN, cranial nerveCPA, cerebellopontine angleFN, facial nerveGTR, gloss total resectionH-B, House-BrackmannHPS, hearing preservation surgeryNTR, near-total resectionSRT, stereotactic radiation therapySTR, subtotal resectionVAFE, vascular, adherent, fibrous, and engulfingVS, vestibular schwannoma. Copyright © 2012 by theCongress of Neurological Surgeons.

Authors
Nonaka, Y; Fukushima, T; Watanabe, K; Friedman, AH; Sampson, JH; McElveen, JT; Cunningham, CD; Zomorodi, AR
MLA Citation
Nonaka, Y, Fukushima, T, Watanabe, K, Friedman, AH, Sampson, JH, McElveen, JT, Cunningham, CD, and Zomorodi, AR. "Contemporary surgical management of vestibular schwannomas: Analysis of complications and lessons learned over the past decade." Neurosurgery 72 (2013): ons103-ons115.
Source
scival
Published In
Neurosurgery
Volume
72
Publish Date
2013
Start Page
ons103
End Page
ons115
DOI
10.1227/NEU.0b013e3182752b05

Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: A prospective trial

Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. Methods and Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach. © 2013 Elsevier Inc.

Authors
Cabrera, AR; Cuneo, KC; Desjardins, A; Sampson, JH; McSherry, F; II, JEH; Peters, KB; Allen, K; Hoang, JK; Chang, Z; Craciunescu, O; Vredenburgh, JJ; Friedman, HS; Kirkpatrick, JP
MLA Citation
Cabrera, AR, Cuneo, KC, Desjardins, A, Sampson, JH, McSherry, F, II, JEH, Peters, KB, Allen, K, Hoang, JK, Chang, Z, Craciunescu, O, Vredenburgh, JJ, Friedman, HS, and Kirkpatrick, JP. "Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: A prospective trial." International Journal of Radiation Oncology Biology Physics 86.5 (2013): 873-879.
Source
scival
Published In
International Journal of Radiation Oncology, Biology, Physics
Volume
86
Issue
5
Publish Date
2013
Start Page
873
End Page
879
DOI
10.1016/j.ijrobp.2013.04.029

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. © 2013 Elsevier B.V.

Authors
Choi, BD; Gedeon, PC; Kuan, CT; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, CT, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." Journal of Immunological Methods 395.1-2 (2013): 14-20.
Source
scival
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

Convection enhanced delivery of macromolecules for brain tumors.

The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.

Authors
Mehta, AI; Choi, BD; Ajay, D; Raghavan, R; Brady, M; Friedman, AH; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Choi, BD, Ajay, D, Raghavan, R, Brady, M, Friedman, AH, Pastan, I, Bigner, DD, and Sampson, JH. "Convection enhanced delivery of macromolecules for brain tumors." Current drug discovery technologies 9.4 (December 2012): 305-310.
PMID
22339074
Source
epmc
Published In
Current drug discovery technologies
Volume
9
Issue
4
Publish Date
2012
Start Page
305
End Page
310

Immunotherapy with tumor vaccines for the treatment of malignant gliomas.

With an average life expectancy of 14 months, Glioblastoma multiforme (GBM), is the most aggressive primary brain tumor. Our growing understanding of the immune system and its role in oncogenesis has helped develop cancer vaccines as a promising treatment modality against this disease. What follows is a comprehensive discussion on the history of immunotherapy and the various vaccine based therapies being developed and utilized for the treatment of malignant gliomas.

Authors
Ajay, D; Sanchez-Perez, L; Choi, BD; De Leon, G; Sampson, JH
MLA Citation
Ajay, D, Sanchez-Perez, L, Choi, BD, De Leon, G, and Sampson, JH. "Immunotherapy with tumor vaccines for the treatment of malignant gliomas." Current drug discovery technologies 9.4 (December 2012): 237-255.
PMID
22339070
Source
epmc
Published In
Current drug discovery technologies
Volume
9
Issue
4
Publish Date
2012
Start Page
237
End Page
255
DOI
10.2174/157016312803305933

Regulatory T cells move in when gliomas say "I Do".

Indoleamine 2,3-dioxygenase (IDO) is an enzyme with known immunosuppressive and tolerogenic effects in cancer. Mounting evidence has associated IDO expression with the induction of regulatory T cells (Treg) and malignant progression. IDO inhibition may therefore provide a promising therapeutic approach for glioblastoma, where the need for novel treatment is great.

Authors
Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Choi, BD, Fecci, PE, and Sampson, JH. "Regulatory T cells move in when gliomas say "I Do"." Clin Cancer Res 18.22 (November 15, 2012): 6086-6088.
PMID
23052252
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
18
Issue
22
Publish Date
2012
Start Page
6086
End Page
6088
DOI
10.1158/1078-0432.CCR-12-2801

Enzyme redesign guided by cancer-derived IDH1 mutations.

Mutations in an enzyme can result in a neomorphic catalytic activity in cancers. We applied cancer-associated mutations from isocitrate dehydrogenases to homologous residues in the active sites of homoisocitrate dehydrogenases to derive enzymes that catalyze the conversion of 2-oxoadipate to (R)-2-hydroxyadipate, a critical step for adipic acid production. Thus, we provide a prototypic example of how insights from cancer genome sequencing and functional studies can aid in enzyme redesign.

Authors
Reitman, ZJ; Choi, BD; Spasojevic, I; Bigner, DD; Sampson, JH; Yan, H
MLA Citation
Reitman, ZJ, Choi, BD, Spasojevic, I, Bigner, DD, Sampson, JH, and Yan, H. "Enzyme redesign guided by cancer-derived IDH1 mutations." Nat Chem Biol 8.11 (November 2012): 887-889.
PMID
23001033
Source
pubmed
Published In
Nature Chemical Biology
Volume
8
Issue
11
Publish Date
2012
Start Page
887
End Page
889
DOI
10.1038/nchembio.1065

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Authors
Reardon, DA; Herndon, JE; Peters, KB; Desjardins, A; Coan, A; Lou, E; Sumrall, AL; Turner, S; Lipp, ES; Sathornsumetee, S; Rich, JN; Sampson, JH; Friedman, AH; Boulton, ST; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, DA, Herndon, JE, Peters, KB, Desjardins, A, Coan, A, Lou, E, Sumrall, AL, Turner, S, Lipp, ES, Sathornsumetee, S, Rich, JN, Sampson, JH, Friedman, AH, Boulton, ST, Bigner, DD, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients." Br J Cancer 107.9 (October 23, 2012): 1481-1487.
PMID
23037712
Source
pubmed
Published In
British Journal of Cancer
Volume
107
Issue
9
Publish Date
2012
Start Page
1481
End Page
1487
DOI
10.1038/bjc.2012.415

FEASIBILITY OF AMPLIFIED CD133((+)) BRAIN TUMOR STEM CELL RNA-PULSED DENDRITIC CELLS FOR THE TREATMENT OF PATIENTS WITH RECURRENT GLIOBLASTOMA

Authors
Archer, GE; Xie, W; Norberg, P; Dechkovskaia, A; Friedman, A; Bigner, DD; Mitchell, DA; Sampson, JH; Boczkowski, D
MLA Citation
Archer, GE, Xie, W, Norberg, P, Dechkovskaia, A, Friedman, A, Bigner, DD, Mitchell, DA, Sampson, JH, and Boczkowski, D. "FEASIBILITY OF AMPLIFIED CD133((+)) BRAIN TUMOR STEM CELL RNA-PULSED DENDRITIC CELLS FOR THE TREATMENT OF PATIENTS WITH RECURRENT GLIOBLASTOMA." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
49
End Page
49

EX VIVO GENERATION OF CENTRAL MEMORY-LIKE ANTI-TUMOR T CELLS TO TREAT MALIGNANT BRAIN TUMORS

Authors
Yang, S; Archer, GE; Miao, H; Cui, X; Xie, W; Snyder, D; Pretorian, AJ; Dechkovskaia, A; Reap, E; Perez, LAS; Norberg, P; Schmittling, R; Mitchell, DA; Sampson, JH
MLA Citation
Yang, S, Archer, GE, Miao, H, Cui, X, Xie, W, Snyder, D, Pretorian, AJ, Dechkovskaia, A, Reap, E, Perez, LAS, Norberg, P, Schmittling, R, Mitchell, DA, and Sampson, JH. "EX VIVO GENERATION OF CENTRAL MEMORY-LIKE ANTI-TUMOR T CELLS TO TREAT MALIGNANT BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
45
End Page
45

ASSESSMENT OF INTRATUMORAL TREGS AND CLINICAL OUTCOMES IN PRIMARY AND RECURRENT GLIOBLASTOMA

Authors
Sayour, EJ; McLendon, P; Reynolds, R; Bigner, DD; Sampson, JH; McLendon, R; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, Reynolds, R, Bigner, DD, Sampson, JH, McLendon, R, and Mitchell, DA. "ASSESSMENT OF INTRATUMORAL TREGS AND CLINICAL OUTCOMES IN PRIMARY AND RECURRENT GLIOBLASTOMA." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
39
End Page
39

NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY

Authors
Desjardins, A; Peters, KB; II, HJE; Bailey, LA; Alderson, LM; Ranjan, T; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Peters, KB, II, HJE, Bailey, LA, Alderson, LM, Ranjan, T, Sampson, JH, Friedman, AH, Bigner, DD, Friedman, HS, and Vredenburgh, JJ. "NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
104
End Page
104

DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS

Authors
Sayour, EJ; Sanchez-Perez, L; Pham, C; Snyder, D; Xie, W; Cui, X; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, Sanchez-Perez, L, Pham, C, Snyder, D, Xie, W, Cui, X, Bigner, DD, Sampson, JH, and Mitchell, DA. "DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
39
End Page
39

INTRAVENOUS TREATMENT WITH AN ENDOTHELIAL GROWTH FACTOR RECEPTOR VIII-TARGETED BISPECIFIC ANTIBODY SUCCESSFULLY TREATS WELL-ESTABLISHED BRAIN TUMORS

Authors
Choi, BD; Kuan, C-T; Cai, M; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Kuan, C-T, Cai, M, Bigner, DD, and Sampson, JH. "INTRAVENOUS TREATMENT WITH AN ENDOTHELIAL GROWTH FACTOR RECEPTOR VIII-TARGETED BISPECIFIC ANTIBODY SUCCESSFULLY TREATS WELL-ESTABLISHED BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
38
End Page
39

MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS

Authors
Sanchez-Perez, L; Choi, B; Snyder, D; Cui, X; Schmittling, RJ; Flores, C; Johnson, L; Archer, GA; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, B, Snyder, D, Cui, X, Schmittling, RJ, Flores, C, Johnson, L, Archer, GA, Bigner, DD, Mitchell, DA, and Sampson, JH. "MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
40
End Page
40

DEVELOPMENT OF IMMUNOCOMPETENT SYNGENEIC MODELS OF MEDULLOBLASTOMA FOR EVALUATION OF IMMUNOTHERAPY

Authors
Pham, CD; Flores, C; Snyder, D; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Pham, CD, Flores, C, Snyder, D, Bigner, DD, Sampson, JH, and Mitchell, DA. "DEVELOPMENT OF IMMUNOCOMPETENT SYNGENEIC MODELS OF MEDULLOBLASTOMA FOR EVALUATION OF IMMUNOTHERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
163
End Page
163

ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY

Authors
Flores, CT; Snyder, D; Sanchez-Perez, L; Pham, C; Friedman, H; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Flores, CT, Snyder, D, Sanchez-Perez, L, Pham, C, Friedman, H, Bigner, DD, Sampson, JH, and Mitchell, DA. "ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
35
End Page
35

NEUROKININ-1 RECEPTOR: A POTENTIAL TARGET TO INHIBIT PEDIATRIC GLIOBLASTOMAS

Authors
Brown, KE; Keir, ST; Sampson, JH; Bigner, DD; Kwatra, MM
MLA Citation
Brown, KE, Keir, ST, Sampson, JH, Bigner, DD, and Kwatra, MM. "NEUROKININ-1 RECEPTOR: A POTENTIAL TARGET TO INHIBIT PEDIATRIC GLIOBLASTOMAS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
17
End Page
18

TARGETING CYTOMEGALOVIRUS ANTIGENS FOR GLIOBLASTOMA IMMUNOTHERAPY

Authors
Nair, S; Schmittling, R; Boczkowski, D; Archer, G; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Nair, S, Schmittling, R, Boczkowski, D, Archer, G, Bigner, DD, Sampson, JH, and Mitchell, DA. "TARGETING CYTOMEGALOVIRUS ANTIGENS FOR GLIOBLASTOMA IMMUNOTHERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
32
End Page
32

Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radiographic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, KB; Sathornsumetee, S; Threatt, S; Sampson, JH; Herndon, JE; Coan, A; McSherry, F; Rich, JN; McLendon, RE; Zhang, S; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, KB, Sathornsumetee, S, Threatt, S, Sampson, JH, Herndon, JE, Coan, A, McSherry, F, Rich, JN, McLendon, RE, Zhang, S, and Friedman, HS. "Phase 1 trial of dasatinib plus erlotinib in adults with recurrent malignant glioma." J Neurooncol 108.3 (July 2012): 499-506.
PMID
22407177
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
108
Issue
3
Publish Date
2012
Start Page
499
End Page
506
DOI
10.1007/s11060-012-0848-x

Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme.

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.

Authors
Cabrera, AR; Cuneo, KC; Vredenburgh, JJ; Sampson, JH; Kirkpatrick, JP
MLA Citation
Cabrera, AR, Cuneo, KC, Vredenburgh, JJ, Sampson, JH, and Kirkpatrick, JP. "Stereotactic radiosurgery and bevacizumab for recurrent glioblastoma multiforme." J Natl Compr Canc Netw 10.6 (June 1, 2012): 695-699.
PMID
22679114
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
10
Issue
6
Publish Date
2012
Start Page
695
End Page
699

Resection and survival.

Authors
Sampson, JH; Hoang, JK
MLA Citation
Sampson, JH, and Hoang, JK. "Resection and survival." J Neurosurg 116.6 (June 2012): 1169-1170.
PMID
22424561
Source
pubmed
Published In
Journal of neurosurgery
Volume
116
Issue
6
Publish Date
2012
Start Page
1169
End Page
1170
DOI
10.3171/2011.10.JNS111437

Stereotactic radiotherapy for malignancies involving the trigeminal and facial nerves.

Involvement of a cranial nerve caries a poor prognosis for many malignancies. Recurrent or residual disease in the trigeminal or facial nerve after primary therapy poses a challenge due to the location of the nerve in the skull base, the proximity to the brain, brainstem, cavernous sinus, and optic apparatus and the resulting complex geometry. Surgical resection caries a high risk of morbidity and is often not an option for these patients. Stereotactic radiosurgery and radiotherapy are potential treatment options for patients with cancer involving the trigeminal or facial nerve. These techniques can deliver high doses of radiation to complex volumes while sparing adjacent critical structures. In the current study, seven cases of cancer involving the trigeminal or facial nerve are presented. These patients had unresectable recurrent or residual disease after definitive local therapy. Each patient was treated with stereotactic radiation therapy using a linear accelerator based system. A multidisciplinary approach including neuroradiology and surgical oncology was used to delineate target volumes. Treatment was well tolerated with no acute grade 3 or higher toxicity. One patient who was reirradiated experienced cerebral radionecrosis with mild symptoms. Four of the seven patients treated had no evidence of disease after a median follow up of 12 months (range 2-24 months). A dosimetric analysis was performed to compare intensity modulated fractionated stereotactic radiation therapy (IM-FSRT) to a 3D conformal technique. The dose to 90% (D90) of the brainstem was lower with the IM-FSRT plan by a mean of 13.5 Gy. The D95 to the ipsilateral optic nerve was also reduced with IM-FSRT by 12.2 Gy and the D95 for the optic chiasm was lower with FSRT by 16.3 Gy. Treatment of malignancies involving a cranial nerve requires a multidisciplinary approach. Use of an IM-FSRT technique with a micro-multileaf collimator resulted in a lower dose to the brainstem, optic nerves and chiasm for each case examined.

Authors
Cuneo, KC; Zagar, TM; Brizel, DM; Yoo, DS; Hoang, JK; Chang, Z; Wang, Z; Yin, FF; Das, SK; Green, S; Ready, N; Bhatti, MT; Kaylie, DM; Becker, A; Sampson, JH; Kirkpatrick, JP
MLA Citation
Cuneo, KC, Zagar, TM, Brizel, DM, Yoo, DS, Hoang, JK, Chang, Z, Wang, Z, Yin, FF, Das, SK, Green, S, Ready, N, Bhatti, MT, Kaylie, DM, Becker, A, Sampson, JH, and Kirkpatrick, JP. "Stereotactic radiotherapy for malignancies involving the trigeminal and facial nerves." Technol Cancer Res Treat 11.3 (June 2012): 221-228.
PMID
22468993
Source
pubmed
Published In
Technology in cancer research & treatment
Volume
11
Issue
3
Publish Date
2012
Start Page
221
End Page
228
DOI
10.7785/tcrt.2012.500290

The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM).

Authors
Friedman, HS; Desjardins, A; Peters, KB; Reardon, DA; Kirkpatrick, J; Herndon, JE; Coan, AD; Bailey, L; Sampson, JH; Friedman, AH; Vredenburgh, JJ
MLA Citation
Friedman, HS, Desjardins, A, Peters, KB, Reardon, DA, Kirkpatrick, J, Herndon, JE, Coan, AD, Bailey, L, Sampson, JH, Friedman, AH, and Vredenburgh, JJ. "The addition of bevacizumab to temozolomide and radiation therapy followed by bevacizumab, temozolomide, and oral topotecan for newly diagnosed glioblastoma multiforme (GBM)." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas.

PURPOSE: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. METHODS AND MATERIALS: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. RESULTS: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17-0.82) and 0.45 (CI 0.21-0.97). KPS >70 and age <50 years were significantly associated with improved survival. CONCLUSIONS: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach.

Authors
Cuneo, KC; Vredenburgh, JJ; Sampson, JH; Reardon, DA; Desjardins, A; Peters, KB; Friedman, HS; Willett, CG; Kirkpatrick, JP
MLA Citation
Cuneo, KC, Vredenburgh, JJ, Sampson, JH, Reardon, DA, Desjardins, A, Peters, KB, Friedman, HS, Willett, CG, and Kirkpatrick, JP. "Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas." Int J Radiat Oncol Biol Phys 82.5 (April 1, 2012): 2018-2024.
PMID
21489708
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
5
Publish Date
2012
Start Page
2018
End Page
2024
DOI
10.1016/j.ijrobp.2010.12.074

The use of motor mapping to aid resection of eloquent gliomas.

Surgery remains one of the oldest and still most important forms of treatment for patients with glioma. The advantages of surgical resection for glioma must be balanced with the potential of operative morbidity to surrounding eloquent brain. To that end, advances in functional brain mapping allow for safer operations with more aggressive surgical resections. A brief history of motor mapping as well as its present day use in aiding resection of eloquent gliomas is discussed.

Authors
Choi, BD; Mehta, AI; Batich, KA; Friedman, AH; Sampson, JH
MLA Citation
Choi, BD, Mehta, AI, Batich, KA, Friedman, AH, and Sampson, JH. "The use of motor mapping to aid resection of eloquent gliomas." Neurosurg Clin N Am 23.2 (April 2012): 215-vii. (Review)
PMID
22440865
Source
pubmed
Published In
Neurosurgery Clinics of North America
Volume
23
Issue
2
Publish Date
2012
Start Page
215
End Page
vii
DOI
10.1016/j.nec.2012.01.013

Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.

We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naïve, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90-100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

Authors
Reardon, DA; Desjardins, A; Peters, KB; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Bulusu, A; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Bulusu, A, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma." J Neurooncol 107.1 (March 2012): 155-164.
PMID
21986722
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
107
Issue
1
Publish Date
2012
Start Page
155
End Page
164
DOI
10.1007/s11060-011-0722-2

Clinical data simplified.

Authors
Sampson, JH; Herndon, JE; McLendon, RE; Hasselblad, V; Asher, AL; McGirt, MJ; Peterson, ED
MLA Citation
Sampson, JH, Herndon, JE, McLendon, RE, Hasselblad, V, Asher, AL, McGirt, MJ, and Peterson, ED. "Clinical data simplified." J Neurosurg 116.2 (February 2012): 346-348.
PMID
22054209
Source
pubmed
Published In
Journal of neurosurgery
Volume
116
Issue
2
Publish Date
2012
Start Page
346
End Page
348
DOI
10.3171/2011.5.JNS11279

Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme.

PURPOSE: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m(2) daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. RESULTS: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. CONCLUSIONS: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM.

Authors
Vredenburgh, JJ; Desjardins, A; Kirkpatrick, JP; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Bailey, L; Threatt, S; Sampson, J; Friedman, A; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Kirkpatrick, JP, Reardon, DA, Peters, KB, Herndon, JE, Marcello, J, Bailey, L, Threatt, S, Sampson, J, Friedman, A, and Friedman, HS. "Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme." Int J Radiat Oncol Biol Phys 82.1 (January 1, 2012): 58-66.
PMID
21036490
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
82
Issue
1
Publish Date
2012
Start Page
58
End Page
66
DOI
10.1016/j.ijrobp.2010.08.058

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥ 10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.

Authors
Reardon, DA; Norden, AD; Desjardins, A; Vredenburgh, JJ; Herndon, JE; Coan, A; Sampson, JH; Gururangan, S; Peters, KB; McLendon, RE; Norfleet, JA; Lipp, ES; Drappatz, J; Wen, PY; Friedman, HS
MLA Citation
Reardon, DA, Norden, AD, Desjardins, A, Vredenburgh, JJ, Herndon, JE, Coan, A, Sampson, JH, Gururangan, S, Peters, KB, McLendon, RE, Norfleet, JA, Lipp, ES, Drappatz, J, Wen, PY, and Friedman, HS. "Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma." J Neurooncol 106.2 (January 2012): 409-415.
PMID
21938530
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
106
Issue
2
Publish Date
2012
Start Page
409
End Page
415
DOI
10.1007/s11060-011-0687-1

Toxin-based targeted therapy for malignant brain tumors.

Despite advances in conventional treatment modalities for malignant brain tumors-surgery, radiotherapy, and chemotherapy-the prognosis for patients with high-grade astrocytic tumor remains dismal. The highly heterogeneous and diffuse nature of astrocytic tumors calls for the development of novel therapies. Advances in genomic and proteomic research indicate that treatment of brain tumor patients can be increasingly personalized according to the characteristics of the targeted tumor and its environment. Consequently, during the last two decades, a novel class of investigative drug candidates for the treatment of central nervous system neoplasia has emerged: recombinant fusion protein conjugates armed with cytotoxic agents targeting tumor-specific antigens. The clinical applicability of the tumor-antigen-directed cytotoxic proteins as a safe and viable therapy for brain tumors is being investigated. Thus far, results from ongoing clinical trials are encouraging, as disease stabilization and patient survival prolongation have been observed in at least 109 cases. This paper summarizes the major findings pertaining to treatment with the different antiglioma cytotoxins at the preclinical and clinical stages.

Authors
Chandramohan, V; Sampson, JH; Pastan, I; Bigner, DD
MLA Citation
Chandramohan, V, Sampson, JH, Pastan, I, and Bigner, DD. "Toxin-based targeted therapy for malignant brain tumors." Clinical & developmental immunology 2012 (January 2012): 480429-. (Review)
PMID
22400035
Source
epmc
Published In
Clinical & Developmental Immunology (Hindawi)
Volume
2012
Publish Date
2012
Start Page
480429
DOI
10.1155/2012/480429

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.

Authors
Sampson, JH; Schmittling, RJ; Archer, GE; Congdon, KL; Nair, SK; Reap, EA; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Mitchell, DA
MLA Citation
Sampson, JH, Schmittling, RJ, Archer, GE, Congdon, KL, Nair, SK, Reap, EA, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Mitchell, DA. "A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma." PLoS One 7.2 (2012): e31046-.
PMID
22383993
Source
pubmed
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31046
DOI
10.1371/journal.pone.0031046

Disparities in care

Authors
Sampson, JH; Bagley, CA; Sr, BSC
MLA Citation
Sampson, JH, Bagley, CA, and Sr, BSC. "Disparities in care." Journal of Neurosurgery 116.2 (2012): 280-281.
PMID
21740120
Source
scival
Published In
Journal of neurosurgery
Volume
116
Issue
2
Publish Date
2012
Start Page
280
End Page
281
DOI
10.3171/2011.5.JNS11410

Avastin: More questions than answers...

Authors
Desjardins, A; Sampson, JH
MLA Citation
Desjardins, A, and Sampson, JH. "Avastin: More questions than answers.." Journal of Neurosurgery 116.2 (2012): 336-339.
PMID
22035270
Source
scival
Published In
Journal of neurosurgery
Volume
116
Issue
2
Publish Date
2012
Start Page
336
End Page
339
DOI
10.3171/2011.8.JNS111107

Convection-enhanced delivery

Authors
Sampson, JH
MLA Citation
Sampson, JH. "Convection-enhanced delivery." Journal of Neurosurgery 117.6 (2012): 1126-1127.
PMID
22998062
Source
scival
Published In
Journal of neurosurgery
Volume
117
Issue
6
Publish Date
2012
Start Page
1126
End Page
1127
DOI
10.3171/2012.1.JNS12208

The limitations of imaging response criteria

Authors
Mehta, VAI; Sampson, JH
MLA Citation
Mehta, VAI, and Sampson, JH. "The limitations of imaging response criteria." The Lancet Oncology 13.11 (2012): 1064-1065.
PMID
23116995
Source
scival
Published In
The Lancet Oncology
Volume
13
Issue
11
Publish Date
2012
Start Page
1064
End Page
1065
DOI
10.1016/S1470-2045(12)70458-8

Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) working group

BACKGROUND: The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments. OBJECTIVE: To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas. METHODS: The Surgery Working Group of RANO identified surgically related end-point evaluation problems that were not addressed in the original Macdonald criteria, performed an extensive literature review, and used a consensus-building process to develop recommendations for how to address these issues in the setting of clinical trials. RESULTS: Recommendations were formulated for surgically related issues, including imaging changes associated with surgical resection or surgically mediated adjuvant local therapies, the determination of progression in the setting where all enhancing tumor has been removed, and how new enhancement should be interpreted in the setting where local therapies that are known to produce nonspecific enhancement have been used. Additionally, the terminology used to describe the completeness of surgical resections has been recognized to be inconsistently applied to enhancing vs nonenhancing tumors, and a new set of descriptors is proposed. CONCLUSION: The RANO process is intended to produce end-point criteria for clinical trials that take into account the effects of prior and ongoing therapies. The RANO criteria will continue to evolve as new therapies and technologies are introduced into clinical trial and/or practice. Copyright © 2011 by the Congress of Neurological Surgeons.

Authors
Vogelbaum, MA; Jost, S; Aghi, MK; Heimberger, AB; Sampson, JH; Wen, PY; MacDonald, DR; Bent, MJVD; Chang, SM
MLA Citation
Vogelbaum, MA, Jost, S, Aghi, MK, Heimberger, AB, Sampson, JH, Wen, PY, MacDonald, DR, Bent, MJVD, and Chang, SM. "Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) working group." Neurosurgery 70.1 (2012): 234-243.
PMID
21593697
Source
scival
Published In
Neurosurgery
Volume
70
Issue
1
Publish Date
2012
Start Page
234
End Page
243
DOI
10.1227/NEU.0b013e318223f5a7

Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

BACKGROUND: The efficacy of carboplatin, irinotecan, and bevacizumab among recurrent glioblastoma (GBM) patients after prior progression on bevacizumab therapy in a phase 2, open-label, single-arm trial was evaluated. METHODS: Eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day 1, whereas bevacizumab (10 mg/kg) and irinotecan (340 mg/m(2) for patients on CYP3A enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m(2) for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first 2 cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, noncompliance, or voluntary withdrawal. The primary end point was progression-free survival at 6 months (PFS-6), and secondary end points included safety and median overall survival (OS). RESULTS: All patients had progression on at least 1 prior bevacizumab regimen and 56% enrolled after either second or third overall progression. The median OS was 5.8 months (95% confidence interval [CI], 4.0-7.0 months) and PFS-6 rate was 16% (95% CI, 5.0%-32.5%). The most common grade 3 or 4 events were hematologic and occurred in 29% of cycles. Nine patients (38%) required dose modification. There were no treatment-related deaths. CONCLUSIONS: Carboplatin, irinotecan, and bevacizumab was associated with modest activity and adequate safety among recurrent GBM patients who progressed on bevacizumab previously.

Authors
Reardon, DA; Desjardins, A; Peters, KB; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Coan, A; Threatt, S; Friedman, AH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, KB, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Coan, A, Threatt, S, Friedman, AH, and Friedman, HS. "Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." Cancer 117.23 (December 1, 2011): 5351-5358.
PMID
21590689
Source
pubmed
Published In
Cancer
Volume
117
Issue
23
Publish Date
2011
Start Page
5351
End Page
5358
DOI
10.1002/cncr.26188

CYTOMEGALOVIRUS-SPECIFIC IMMUNE DEFICITS IN PATIENTS WITH GBM

Authors
Johnson, LA; Archer, GE; Nair, SK; Schmittling, R; Reap, E; Sampson, JH
MLA Citation
Johnson, LA, Archer, GE, Nair, SK, Schmittling, R, Reap, E, and Sampson, JH. "CYTOMEGALOVIRUS-SPECIFIC IMMUNE DEFICITS IN PATIENTS WITH GBM." November 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
39
End Page
39

DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA

Authors
Mitchell, DA; Archer, GE; Friedman, HS; Herndon, JE; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Archer, GE, Friedman, HS, Herndon, JE, Bigner, DD, and Sampson, JH. "DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA." NEURO-ONCOLOGY 13 (November 2011): 39-39.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
39
End Page
39

Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma.

Authors
Lou, E; Turner, S; Sumrall, A; Reardon, DA; Desjardins, A; Peters, KB; Sampson, JH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Lou, E, Turner, S, Sumrall, A, Reardon, DA, Desjardins, A, Peters, KB, Sampson, JH, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab-induced reversible posterior leukoencephalopathy syndrome and successful retreatment in a patient with glioblastoma." J Clin Oncol 29.28 (October 1, 2011): e739-e742.
PMID
21900098
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
29
Issue
28
Publish Date
2011
Start Page
e739
End Page
e742
DOI
10.1200/JCO.2011.36.1865

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Cui, X, Schmittling, RJ, Sanchez-Perez, L, Snyder, DJ, Congdon, KL, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans." Blood 118.11 (September 15, 2011): 3003-3012.
PMID
21768296
Source
pubmed
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Convection-enhanced delivery.

Authors
Sampson, JH; Raghavan, R; Brady, M; Friedman, AH; Bigner, D
MLA Citation
Sampson, JH, Raghavan, R, Brady, M, Friedman, AH, and Bigner, D. "Convection-enhanced delivery." J Neurosurg 115.3 (September 2011): 463-464.
PMID
21619413
Source
pubmed
Published In
Journal of neurosurgery
Volume
115
Issue
3
Publish Date
2011
Start Page
463
End Page
464
DOI
10.3171/2010.11.JNS101801

Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans.

BACKGROUND: Convection-enhanced delivery (CED) permits site-specific therapeutic drug delivery within interstitial spaces at increased dosages through circumvention of the blood-brain barrier. CED is currently limited by suboptimal methodologies for monitoring the delivery of therapeutic agents that would permit technical optimization and enhanced therapeutic efficacy. OBJECTIVE: To determine whether a readily available small-molecule MRI contrast agent, gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), could effectively track the distribution of larger therapeutic agents. METHODS: Gd-DTPA was coinfused with the larger molecular tracer, I-labeled human serum albumin (I-HSA), during CED of an EGFRvIII-specific immunotoxin as part of treatment for a patient with glioblastoma. RESULTS: Infusion of both tracers was safe in this patient. Analysis of both Gd-DTPA and I-HSA during and after infusion revealed a high degree of anatomical and volumetric overlap. CONCLUSION: Gd-DTPA may be able to accurately demonstrate the anatomic and volumetric distribution of large molecules used for antitumor therapy with high resolution and in combination with fluid-attenuated inversion recovery (FLAIR) imaging, and provide additional information about leaks into cerebrospinal fluid spaces and resection cavities. Similar studies should be performed in additional patients to validate our findings and help refine the methodologies we used.

Authors
Sampson, JH; Brady, M; Raghavan, R; Mehta, AI; Friedman, AH; Reardon, DA; Petry, NA; Barboriak, DP; Wong, TZ; Zalutsky, MR; Lally-Goss, D; Bigner, DD
MLA Citation
Sampson, JH, Brady, M, Raghavan, R, Mehta, AI, Friedman, AH, Reardon, DA, Petry, NA, Barboriak, DP, Wong, TZ, Zalutsky, MR, Lally-Goss, D, and Bigner, DD. "Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans." Neurosurgery 69.3 (September 2011): 668-676.
PMID
21430586
Source
pubmed
Published In
Neurosurgery
Volume
69
Issue
3
Publish Date
2011
Start Page
668
End Page
676
DOI
10.1227/NEU.0b013e3182181ba8

Our failure to advance new treatments for glioma to market.

Authors
Sampson, JH; Kaminski, TJ; Schulman, KA
MLA Citation
Sampson, JH, Kaminski, TJ, and Schulman, KA. "Our failure to advance new treatments for glioma to market." J Neurosurg 115.2 (August 2011): 245-247.
PMID
21568655
Source
pubmed
Published In
Journal of neurosurgery
Volume
115
Issue
2
Publish Date
2011
Start Page
245
End Page
247
DOI
10.3171/2010.11.JNS101436

Epidemiology.

Authors
Sampson, JH; Herndon, JE; Friedman, AH; Abernethy, AP
MLA Citation
Sampson, JH, Herndon, JE, Friedman, AH, and Abernethy, AP. "Epidemiology." J Neurosurg 115.2 (August 2011): 256-257.
PMID
21529133
Source
pubmed
Published In
Journal of neurosurgery
Volume
115
Issue
2
Publish Date
2011
Start Page
256
End Page
257
DOI
10.3171/2011.1.JNS102066

Is cytomegalovirus a therapeutic target in glioblastoma?

Several investigators have now demonstrated the expression of genes unique to cytomegalovirus (CMV) in malignant gliomas. Many of these genes promote oncogenesis, alter tumor microenvironment, and serve as immunologic targets. Is the level of CMV infection within tumor cells sufficient to drive important oncogenic or immunosuppressive processes? Can CMV serve as a target for therapeutic intervention?

Authors
Sampson, JH; Mitchell, DA
MLA Citation
Sampson, JH, and Mitchell, DA. "Is cytomegalovirus a therapeutic target in glioblastoma?." Clin Cancer Res 17.14 (July 15, 2011): 4619-4621.
PMID
21632859
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
4619
End Page
4621
DOI
10.1158/1078-0432.CCR-11-0992

Bispecific antibodies engage T cells for antitumor immunotherapy.

INTRODUCTION: Although considerable evidence supports the hypothesis that T cells play a critical role in the immune response against cancer, the ability to mount and sustain tumor-specific cellular responses in vivo remains a challenge. A strategy that harnesses the cytotoxic advantage of T cell therapy is the use of bispecific antibodies designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex, but only in the presence of a tumor antigen. While antibody constructs with dual specificity were first described as anticancer therapeutics over 25 years ago, it was not until recently that one subclass of bispecific single-chain antibody, the bispecific T cell engager (BiTE), emerged as superior to previous iterations in achieving efficacy in animal models and early clinical trials. AREAS COVERED: The evolution of bispecific antibodies in antitumor immunotherapy is reviewed and the greatest hurdles impeding their clinical translation are discussed, specifically in the context of immunoprivileged sites as is the case for intracerebral malignancy. EXPERT OPINION: The BiTE platform has great potential in the treatment of malignant disease. Despite burgeoning interest in bispecific antibodies and permutations thereof, the issues of stability and cost-effective production persist as obstacles.

Authors
Choi, BD; Cai, M; Bigner, DD; Mehta, AI; Kuan, C-T; Sampson, JH
MLA Citation
Choi, BD, Cai, M, Bigner, DD, Mehta, AI, Kuan, C-T, and Sampson, JH. "Bispecific antibodies engage T cells for antitumor immunotherapy." Expert Opin Biol Ther 11.7 (July 2011): 843-853. (Review)
PMID
21449821
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
11
Issue
7
Publish Date
2011
Start Page
843
End Page
853
DOI
10.1517/14712598.2011.572874

The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma.

PURPOSE: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective. EXPERIMENTAL DESIGN: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent. RESULTS: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2-25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). CONCLUSION: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Kirkpatrick, JP; Sampson, JH; Bailey, L; Threatt, S; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Reardon, DA, Peters, KB, Herndon, JE, Marcello, J, Kirkpatrick, JP, Sampson, JH, Bailey, L, Threatt, S, Friedman, AH, Bigner, DD, and Friedman, HS. "The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma." Clin Cancer Res 17.12 (June 15, 2011): 4119-4124.
PMID
21531816
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
12
Publish Date
2011
Start Page
4119
End Page
4124
DOI
10.1158/1078-0432.CCR-11-0120

Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy.

We evaluated the efficacy of metronomic etoposide or temozolomide administered with bevacizumab among recurrent glioblastoma (GBM) patients who progressed on prior bevacizumab therapy in a phase 2, open-label, two-arm trial. Twenty-three patients received bevacizumab (10 mg/kg) every 2 weeks with either oral etoposide (50 mg/m2) daily for 21 consecutive days each month or daily temozolomide (50 mg/m2). The primary endpoint was 6-month progression-free survival (PFS-6) and secondary endpoints included safety and overall survival. Both the etoposide and temozolomide arms of the study closed at the interim analysis due to lack of adequate anti-tumor activity. No radiographic responses were observed. Although 12 patients (52%) achieved stable disease, PFS-6 was 4.4% and the median PFS was 7.3 weeks. The only grade 4 adverse event was reversible neutropenia. Grade 3 toxicities included fatigue (n = 2) and infection (n = 1). Metronomic etoposide or temozolomide is ineffective when administered with bevacizumab among recurrent GBM patients who have progressed on prior bevacizumab therapy. Alternative treatment strategies remain critically needed for this indication.

Authors
Reardon, DA; Desjardins, A; Peters, K; Gururangan, S; Sampson, J; Rich, JN; McLendon, R; Herndon, JE; Marcello, J; Threatt, S; Friedman, AH; Vredenburgh, JJ; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Peters, K, Gururangan, S, Sampson, J, Rich, JN, McLendon, R, Herndon, JE, Marcello, J, Threatt, S, Friedman, AH, Vredenburgh, JJ, and Friedman, HS. "Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy." J Neurooncol 103.2 (June 2011): 371-379.
PMID
20853132
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
103
Issue
2
Publish Date
2011
Start Page
371
End Page
379
DOI
10.1007/s11060-010-0403-6

Safety results from a prospective study of concurrent radiosurgery and bevacizumab for recurrent malignant glioma.

Authors
Cuneo, KC; Cabrera, AR; Sampson, JH; Allen, KJ; Vredenburgh, JJ; Peters, K; Chang, Z; Herndon, JE; Desjardins, A; Reardon, DA; Kirkpatrick, J
MLA Citation
Cuneo, KC, Cabrera, AR, Sampson, JH, Allen, KJ, Vredenburgh, JJ, Peters, K, Chang, Z, Herndon, JE, Desjardins, A, Reardon, DA, and Kirkpatrick, J. "Safety results from a prospective study of concurrent radiosurgery and bevacizumab for recurrent malignant glioma." JOURNAL OF CLINICAL ONCOLOGY 29.15 (May 20, 2011).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
29
Issue
15
Publish Date
2011

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Authors
Reardon, DA; Turner, S; Peters, KB; Desjardins, A; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Jones, LW; Kirkpatrick, JP; Friedman, AH; Vredenburgh, JJ; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Turner, S, Peters, KB, Desjardins, A, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Jones, LW, Kirkpatrick, JP, Friedman, AH, Vredenburgh, JJ, Bigner, DD, and Friedman, HS. "A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma." J Natl Compr Canc Netw 9.4 (April 2011): 414-427. (Review)
PMID
21464146
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
4
Publish Date
2011
Start Page
414
End Page
427

Monitoring radiographic brain tumor progression.

Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to detect tumor progression radiographically remains inadequate. Despite the advanced imaging techniques, detecting tumor progression continues to be a clinical challenge. Here we review the different criteria used to detect tumor progression, and highlight the inherent challenges with detection of progression.

Authors
Mehta, AI; Kanaly, CW; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Kanaly, CW, Friedman, AH, Bigner, DD, and Sampson, JH. "Monitoring radiographic brain tumor progression." Toxins (Basel) 3.3 (March 2011): 191-200. (Review)
PMID
22069705
Source
pubmed
Published In
Toxins
Volume
3
Issue
3
Publish Date
2011
Start Page
191
End Page
200
DOI
10.3390/toxins3030191

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Authors
Sampson, JH; Aldape, KD; Archer, GE; Coan, A; Desjardins, A; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, R; Shi, W; Vredenburgh, JJ; Bigner, DD; Heimberger, AB
MLA Citation
Sampson, JH, Aldape, KD, Archer, GE, Coan, A, Desjardins, A, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, R, Shi, W, Vredenburgh, JJ, Bigner, DD, and Heimberger, AB. "Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma." Neuro Oncol 13.3 (March 2011): 324-333.
PMID
21149254
Source
pubmed
Published In
Neuro-Oncology
Volume
13
Issue
3
Publish Date
2011
Start Page
324
End Page
333
DOI
10.1093/neuonc/noq157

Imaging of convection enhanced delivery of toxins in humans.

Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field.

Authors
Mehta, AI; Choi, BD; Raghavan, R; Brady, M; Friedman, AH; Bigner, DD; Pastan, I; Sampson, JH
MLA Citation
Mehta, AI, Choi, BD, Raghavan, R, Brady, M, Friedman, AH, Bigner, DD, Pastan, I, and Sampson, JH. "Imaging of convection enhanced delivery of toxins in humans." Toxins (Basel) 3.3 (March 2011): 201-206. (Review)
PMID
22069706
Source
pubmed
Published In
Toxins
Volume
3
Issue
3
Publish Date
2011
Start Page
201
End Page
206
DOI
10.3390/toxins3030201

Clinical trial end points for high-grade glioma: the evolving landscape.

To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.

Authors
Reardon, DA; Galanis, E; DeGroot, JF; Cloughesy, TF; Wefel, JS; Lamborn, KR; Lassman, AB; Gilbert, MR; Sampson, JH; Wick, W; Chamberlain, MC; Macdonald, DR; Mehta, MP; Vogelbaum, MA; Chang, SM; Van den Bent, MJ; Wen, PY
MLA Citation
Reardon, DA, Galanis, E, DeGroot, JF, Cloughesy, TF, Wefel, JS, Lamborn, KR, Lassman, AB, Gilbert, MR, Sampson, JH, Wick, W, Chamberlain, MC, Macdonald, DR, Mehta, MP, Vogelbaum, MA, Chang, SM, Van den Bent, MJ, and Wen, PY. "Clinical trial end points for high-grade glioma: the evolving landscape." Neuro Oncol 13.3 (March 2011): 353-361. (Review)
PMID
21310734
Source
pubmed
Published In
Neuro-Oncology
Volume
13
Issue
3
Publish Date
2011
Start Page
353
End Page
361
DOI
10.1093/neuonc/noq203

A novel method for volumetric MRI response assessment of enhancing brain tumors.

Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post-contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation.

Authors
Kanaly, CW; Ding, D; Mehta, AI; Waller, AF; Crocker, I; Desjardins, A; Reardon, DA; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Kanaly, CW, Ding, D, Mehta, AI, Waller, AF, Crocker, I, Desjardins, A, Reardon, DA, Friedman, AH, Bigner, DD, and Sampson, JH. "A novel method for volumetric MRI response assessment of enhancing brain tumors. (Published online)" PLoS One 6.1 (January 26, 2011): e16031-.
PMID
21298088
Source
pubmed
Published In
PloS one
Volume
6
Issue
1
Publish Date
2011
Start Page
e16031
DOI
10.1371/journal.pone.0016031

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma.

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Gururangan, S; Sampson, JH; Marcello, J; Herndon, JE; McLendon, RE; Janney, D; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, K, Gururangan, S, Sampson, JH, Marcello, J, Herndon, JE, McLendon, RE, Janney, D, Friedman, AH, Bigner, DD, and Friedman, HS. "Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma." J Neurooncol 101.1 (January 2011): 57-66.
PMID
20443129
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
57
End Page
66
DOI
10.1007/s11060-010-0217-6

Reply to M.S. Lesniak

Authors
Mehta, AI; Persson, O; II, JEH; Archer, GE; McLendon, R; Heimberger, AB; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Persson, O, II, JEH, Archer, GE, McLendon, R, Heimberger, AB, Mitchell, DA, Bigner, DD, and Sampson, JH. "Reply to M.S. Lesniak." Journal of Clinical Oncology 29.22 (2011): 3105-3106.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
22
Publish Date
2011
Start Page
3105
End Page
3106
DOI
10.1200/JCO.2011.35.0256

Reply to M.C. Chamberlain

Authors
Heimberger, AB; Bigner, DD; II, JEH; Sampson, JH
MLA Citation
Heimberger, AB, Bigner, DD, II, JEH, and Sampson, JH. "Reply to M.C. Chamberlain." Journal of Clinical Oncology 29.17 (2011): e519-e520.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
17
Publish Date
2011
Start Page
e519
End Page
e520
DOI
10.1200/JCO.2010.34.1453

Radiographic progression of a Chiari I malformation after minor head trauma: Final increment of obstruction to create pathophysiology

Introduction The Chiari I malformation is a rare pathological condition that is characterized by a downward herniation of the cerebellar tonsils and brainstem through the foramen magnum. The transformation from an asymptomatic to symptomatic Chiari I malformation is poorly understood, but the major inciting factor associated with this transformation has been trauma. Here, we report the first documented case of radiographic and clinical progression from an asymptomatic to symptomatic Chiari I malformation after a traumatic injury and provide a possible pathologic mechanism related to an occult cerebrospinal fluid (CSF) leak. Clinical Presentation A 32 year old woman presented with a history of intermittent headaches and an MRI demonstrating 8 mm of tonsillar decent. After a traumatic motor vehicle collision, she developed bifrontal tussive headaches and neck and arm burning numbness with progression of tonsillar descent to 12 mm. Intervention The patient underwent a suboccipital craniectomy and partial C1 laminectomy with a duroplasty, in addition to a subpial partial tonsillectomy. Postoperatively, symptoms improved with the exception of persistent positional recurrent headache. Myelogram demonstrated a cervical CSF leak that resolved with an epidural blood patch coincident with resolution of the patients symptoms. Conclusion We document radiographic and symptomatic progression of a Chiari I malformation after a traumatic induction of an occult CSF leak. We believe this may provide some insight into the pathophysiology of Chiari malformation in a subset of patients. © 2011 Surgisphere Corporation.

Authors
Mehta, AI; Grant, GA; Gray, L; Sampson, JH
MLA Citation
Mehta, AI, Grant, GA, Gray, L, and Sampson, JH. "Radiographic progression of a Chiari I malformation after minor head trauma: Final increment of obstruction to create pathophysiology." Journal of Surgical Radiology 2.3 (2011): 290-293.
Source
scival
Published In
Journal of Surgical Radiology
Volume
2
Issue
3
Publish Date
2011
Start Page
290
End Page
293

Resection of vestibular schwannomas

Authors
Sampson, JH; II, JEH
MLA Citation
Sampson, JH, and II, JEH. "Resection of vestibular schwannomas." Journal of Neurosurgery 114.5 (2011): 1216-1217.
PMID
21250806
Source
scival
Published In
Journal of neurosurgery
Volume
114
Issue
5
Publish Date
2011
Start Page
1216
End Page
1217
DOI
10.3171/2010.8.JNS10765

A promising cancer vaccine

Authors
Leon, GD; Mitchell, D; Sampson, J
MLA Citation
Leon, GD, Mitchell, D, and Sampson, J. "A promising cancer vaccine." Future Oncology 7.3 (2011): 331-334.
PMID
21417898
Source
scival
Published In
Future oncology (London, England)
Volume
7
Issue
3
Publish Date
2011
Start Page
331
End Page
334
DOI
10.2217/fon.11.17

A comprehensive outlook on intracerebral therapy of malignant gliomas

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12-15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood-brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel ®, are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM. © 2010 Elsevier Ireland Ltd.

Authors
Buonerba, C; Lorenzo, GD; Marinelli, A; Federico, P; Palmieri, G; Imbimbo, M; Conti, P; Peluso, G; Placido, SD; Sampson, JH
MLA Citation
Buonerba, C, Lorenzo, GD, Marinelli, A, Federico, P, Palmieri, G, Imbimbo, M, Conti, P, Peluso, G, Placido, SD, and Sampson, JH. "A comprehensive outlook on intracerebral therapy of malignant gliomas." Critical Reviews in Oncology/Hematology 80.1 (2011): 54-68.
PMID
20888252
Source
scival
Published In
Critical Reviews in Oncology/Hematology
Volume
80
Issue
1
Publish Date
2011
Start Page
54
End Page
68
DOI
10.1016/j.critrevonc.2010.09.001

Low-grade glioma

Authors
Sampson, JH
MLA Citation
Sampson, JH. "Low-grade glioma." Journal of Neurosurgery 114.3 (2011): 563-564.
PMID
20635855
Source
scival
Published In
Journal of neurosurgery
Volume
114
Issue
3
Publish Date
2011
Start Page
563
End Page
564
DOI
10.3171/2010.1.JNS091940

Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?

With the recent approval by the FDA of an immunotherapy for prostate cancer and another positive immunotherapy trial in melanoma, immunotherapy may finally be coming of age. So what will it take for it to become part of the standard treatment for glioblastoma? To put this question into perspective, we summarize critical background information in neuro-immunology, address immunotherapy clinical trial design, and discuss a number of extrinsic factors that will impact the development of immunotherapy in neuro-oncology. © The Author(s) 2010.

Authors
Heimberger, AB; Sampson, JH
MLA Citation
Heimberger, AB, and Sampson, JH. "Immunotherapy coming of age: What will it take to make it standard of care for glioblastoma?." Neuro-Oncology 13.1 (2011): 3-13.
PMID
21149252
Source
scival
Published In
Neuro-Oncology
Volume
13
Issue
1
Publish Date
2011
Start Page
3
End Page
13
DOI
10.1093/neuonc/noq169

Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study

The PRECISE study used convection enhanced delivery (CED) to infuse IL13-PE38QQR in patients with recurrent glioblastoma multiforme (GBM) and compared survival to Gliadel Wafers (GW). The objectives of this retrospective evaluation were to assess: (1) catheter positioning in relation to imaging features and (2) to examine the potential impact of catheter positioning, overall catheter placement and imaging features on long term clinical outcome in the PRECISE study. Catheter positioning and overall catheter placement were scored and used as a surrogate of adequate placement. Imaging studies obtained on day 43 and day 71 after resection were each retrospectively reviewed. Catheter positioning scores, catheter overall placement scores, local tumor control and imaging change scores were reviewed and correlated using Generalized Linear Mixed Models. Cox PH regression analysis was used to examine whether these imaging based variables predicted overall survival (OS) and progression free survival (PFS) after adjusting for age and KPS. Of 180 patients in the CED group, 20 patients did not undergo gross total resection. Of the remaining 160 patients only 53% of patients had fully conforming catheters in respect to overall placement and 51% had adequate catheter positioning scores. Better catheter positioning scores were not correlated with local tumor control (P = 0.61) or imaging change score (P = 0.86). OS and PFS were not correlated with catheter positioning score (OS: P = 0.53; PFS: P = 0.72 respectively), overall placement score (OS: P = 0.55; PFS: P = 0.35) or imaging changes on day 43 MRI (P = 0.88). Catheter positioning scores and overall catheter placement scores were not associated with clinical outcome in this large prospective trial. © 2010 The Author(s).

Authors
Mueller, S; Polley, M-Y; Lee, B; Kunwar, S; Pedain, C; Wembacher-Schröder, E; Mittermeyer, S; Westphal, M; Sampson, JH; Vogelbaum, MA; Croteau, D; Chang, SM
MLA Citation
Mueller, S, Polley, M-Y, Lee, B, Kunwar, S, Pedain, C, Wembacher-Schröder, E, Mittermeyer, S, Westphal, M, Sampson, JH, Vogelbaum, MA, Croteau, D, and Chang, SM. "Effect of imaging and catheter characteristics on clinical outcome for patients in the PRECISE study." Journal of Neuro-Oncology 101.2 (2011): 267-277.
PMID
20563833
Source
scival
Published In
Journal of Neuro-Oncology
Volume
101
Issue
2
Publish Date
2011
Start Page
267
End Page
277
DOI
10.1007/s11060-010-0255-0

Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma.

PURPOSE: Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS: A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS: There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION: EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.

Authors
Sampson, JH; Heimberger, AB; Archer, GE; Aldape, KD; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, RJ; Shi, W; Vredenburgh, JJ; Bigner, DD
MLA Citation
Sampson, JH, Heimberger, AB, Archer, GE, Aldape, KD, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, RJ, Shi, W, Vredenburgh, JJ, and Bigner, DD. "Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma." J Clin Oncol 28.31 (November 1, 2010): 4722-4729.
PMID
20921459
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
31
Publish Date
2010
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2010.28.6963

USE OF BIOCHEMOTHERAPY AND STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF RECURRENT MALIGNANT GLIOMA

Authors
Cuneo, KC; Vredenburgh, JJ; Sampson, JH; Reardon, DA; Desjardins, A; Peters, KL; Kirkpatrick, JP
MLA Citation
Cuneo, KC, Vredenburgh, JJ, Sampson, JH, Reardon, DA, Desjardins, A, Peters, KL, and Kirkpatrick, JP. "USE OF BIOCHEMOTHERAPY AND STEREOTACTIC RADIOSURGERY IN THE MANAGEMENT OF RECURRENT MALIGNANT GLIOMA." November 2010.
Source
wos-lite
Published In
Neuro-Oncology
Volume
12
Publish Date
2010
Start Page
107
End Page
107

Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321.

OBJECTIVES: While convection enhanced delivery (CED) is an effective delivery method that bypasses the blood-brain barrier, its utility is limited by infusate leakage due to catheter misplacement. Therefore, it is critical to evaluate drug distribution during CED infusion. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a common, readily available MRI contrast agent, which may be able to predict and actively monitor drug distribution. In this study, we assess the long-term safety and toxicity of intracerebrally infused Gd-DTPA along with an experimental targeted agent PRX321. METHODS: Fifty-four immunocompetent rats were implanted with intracerebral cannulas linked to subcutaneously placed osmotic pumps. After pump implantation, the rats were randomized into six groups of nine rats each in order to assess the toxicities of six different concentrations of human serum albumin (HSA) with and without Gd-DTPA and PRX321. The rats were monitored clinically for 6 weeks before they were autopsied and assessed for histological toxicity to their central nervous system (CNS). RESULTS: There was one unexplained death in a group infusing low concentration HSA, Gd-DTPA and PRX321. Upon microscopic examination of the CNS in that animal, no unexpected histological toxicity was found. Additionally, there were no signs of clinical or histological toxicity in any of the remaining rats, which all survived until the end of the 6 week observation period. DISCUSSION: Free Gd-DTPA can be safely infused via CED in a pre-clinical animal model. Future studies should include its use in predicting and actively monitoring CED drug infusions in early phase human clinical trials.

Authors
Ding, D; Kanaly, CW; Cummings, TJ; Herndon, JE; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Cummings, TJ, Herndon, JE, Raghavan, R, and Sampson, JH. "Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321." Neurol Res 32.8 (October 2010): 810-815.
PMID
20021739
Source
pubmed
Published In
Neurological Research
Volume
32
Issue
8
Publish Date
2010
Start Page
810
End Page
815
DOI
10.1179/174367509X12581069052090

Poor drug distribution as a possible explanation for the results of the PRECISE trial.

OBJECT: Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS: Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS: Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS: The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

Authors
Sampson, JH; Archer, G; Pedain, C; Wembacher-Schröder, E; Westphal, M; Kunwar, S; Vogelbaum, MA; Coan, A; Herndon, JE; Raghavan, R; Brady, ML; Reardon, DA; Friedman, AH; Friedman, HS; Rodríguez-Ponce, MI; Chang, SM; Mittermeyer, S; Croteau, D; Puri, RK; PRECISE Trial Investigators,
MLA Citation
Sampson, JH, Archer, G, Pedain, C, Wembacher-Schröder, E, Westphal, M, Kunwar, S, Vogelbaum, MA, Coan, A, Herndon, JE, Raghavan, R, Brady, ML, Reardon, DA, Friedman, AH, Friedman, HS, Rodríguez-Ponce, MI, Chang, SM, Mittermeyer, S, Croteau, D, Puri, RK, and PRECISE Trial Investigators, . "Poor drug distribution as a possible explanation for the results of the PRECISE trial." J Neurosurg 113.2 (August 2010): 301-309.
PMID
20020841
Source
pubmed
Published In
Journal of neurosurgery
Volume
113
Issue
2
Publish Date
2010
Start Page
301
End Page
309
DOI
10.3171/2009.11.JNS091052

Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration.

Temporal paragangliomas are highly vascular tumors treated primarily by surgical resection. However, surgery to remove these tumors is associated with significant morbidity, including cranial nerve dysfunction. Interestingly, these tumors have been shown to express vascular endothelial growth factor (VEGF). A variety of tumors expressing VEGF and the VEGF receptor have been shown to reduce in size and vascularity when treated with the VEGF-specific antibody, bevacizumab (Avastin). We hypothesized that paragangliomas may be treated noninvasively with bevacizumab, either as a primary treatment or as a useful adjuvant to surgical resection or radiation. Thus, our aim was to evaluate the effects of bevacizumab on this patient's paraganglioma. A 36-year-old female presented to us with a 3 month history of positional dizziness, light-headedness, and left ear pulsatile tinnitus and hearing loss. She was found to have a temporal paraganglioma (glomus jugulare tumor) on imaging. Histopathology confirmed significant staining for VEGF. This patient was treated with bevacizumab prior to surgical treatment; radiographic imaging at 3 months, however, showed no significant response. We discuss possible reasons for treatment failure.

Authors
Aliabadi, H; Vredenburgh, JJ; Everson, RG; Desjardins, A; Friedman, HS; McLendon, RE; Tucci, DL; Sampson, JH
MLA Citation
Aliabadi, H, Vredenburgh, JJ, Everson, RG, Desjardins, A, Friedman, HS, McLendon, RE, Tucci, DL, and Sampson, JH. "Bevacizumab fails to treat temporal paraganglioma: discussion and case illustration." J Neurooncol 98.3 (July 2010): 427-430.
PMID
20020179
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
98
Issue
3
Publish Date
2010
Start Page
427
End Page
430
DOI
10.1007/s11060-009-0091-2

Immunotherapy approaches for malignant glioma from 2007 to 2009.

Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential.

Authors
Johnson, LA; Sampson, JH
MLA Citation
Johnson, LA, and Sampson, JH. "Immunotherapy approaches for malignant glioma from 2007 to 2009." Curr Neurol Neurosci Rep 10.4 (July 2010): 259-266. (Review)
PMID
20424975
Source
pubmed
Published In
Current Neurology and Neuroscience Reports
Volume
10
Issue
4
Publish Date
2010
Start Page
259
End Page
266
DOI
10.1007/s11910-010-0111-9

Stereotactic radiosurgery in the treatment of a dural carotid-cavernous fistula.

Because of the success of stereotactic radiosurgery (SRS) in the treatment of cerebral arteriovenous malformations (AVMs), SRS is being applied to the treatment of carotid-cavernous dural arteriovenous fistulas (CCDAVFs) when these lesions are not accessible endovascularly. We report a patient with a CCDAVF that could not be accessed endovascularly on 2 attempts, whose fistula was successfully closed with SRS, a less invasive modality than endovascular embolization. Further experience with SRS in this role will be necessary to determine its utility.

Authors
Chong, GT; Mukundan, S; Kirkpatrick, JP; Zomorodi, A; Sampson, JH; Bhatti, MT
MLA Citation
Chong, GT, Mukundan, S, Kirkpatrick, JP, Zomorodi, A, Sampson, JH, and Bhatti, MT. "Stereotactic radiosurgery in the treatment of a dural carotid-cavernous fistula." J Neuroophthalmol 30.2 (June 2010): 138-144.
PMID
20431489
Source
pubmed
Published In
Journal of Neuro-Ophthalmology
Volume
30
Issue
2
Publish Date
2010
Start Page
138
End Page
144
DOI
10.1097/WNO.0b013e3181ceb3e3

Interim data for ACT III: Phase II trial of PF-04948568 (CDX 110) in combination with temozolomide (TMZ) in patients (pts) with glioblastoma (GBM)

Authors
Lai, R; Recht, LD; Reardon, DA; Paleologos, N; Groves, MD; Rosenfeld, MR; Meech, S; Davis, TA; Pavlov, D; Sampson, JH
MLA Citation
Lai, R, Recht, LD, Reardon, DA, Paleologos, N, Groves, MD, Rosenfeld, MR, Meech, S, Davis, TA, Pavlov, D, and Sampson, JH. "Interim data for ACT III: Phase II trial of PF-04948568 (CDX 110) in combination with temozolomide (TMZ) in patients (pts) with glioblastoma (GBM)." 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

Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1.

A major obstacle in glioblastoma (GBM) therapy is the restrictive nature of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) is a novel method of drug administration which allows direct parenchymal infusion of therapeutics, bypassing the BBB. MR1-1 is a novel recombinant immunotoxin that targets the GBM tumor-specific antigen EGFRvIII and can be delivered via CED infusion. However, drug distribution via CED varies dramatically, which necessitates active monitoring. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a commonly used MRI contrast agent which can be co-infused with therapies using CED and may be useful in monitoring infusion leak and early distribution. Forty immunocompetent rats were implanted with intracerebral cannulas that were connected to osmotic pumps and subsequently randomized into four groups that each received 0.2% human serum albumin (HSA) mixed with a different experimental infusion: (1) 25 ng/ml MR1-1; (2) 0.1 micromol/ml Gd-DTPA; (3) 25 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA; (4) 250 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA. The rats were monitored clinically for 6 weeks then necropsied and histologically assessed for CNS toxicity. All rats survived the entirety of the study without clinical or histological toxicity attributable to the study drugs. There was no statistically significant difference in weight change over time among groups (P > 0.999). MR1-1 co-infused with Gd-DTPA via CED is safe in the long-term setting in a pre-clinical animal model. Our data supports the use of Gd-DTPA, as a surrogate tracer, co-infused with MR1-1 for drug distribution monitoring in patients with GBM.

Authors
Ding, D; Kanaly, CW; Bigner, DD; Cummings, TJ; Herndon, JE; Pastan, I; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Bigner, DD, Cummings, TJ, Herndon, JE, Pastan, I, Raghavan, R, and Sampson, JH. "Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1." J Neurooncol 98.1 (May 2010): 1-7.
PMID
19898744
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
98
Issue
1
Publish Date
2010
Start Page
1
End Page
7
DOI
10.1007/s11060-009-0046-7

Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma.

We evaluated the anti-tumor activity and safety of erlotinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent glioblastoma (GBM) in a phase 2, open-label, single-arm trial. Thirty-two patients received daily erlotinib and sirolimus. The doses of erlotinib and sirolimus were 150 mg and 5 mg for patients not on concurrent CYP3A-inducing anti-epileptics (EIAEDS), and 450 mg and 10 mg for patients on EIAEDS. Evaluations were performed every two months. The primary endpoint was 6-month progression-free survival and secondary endpoints included safety and overall survival. Archival tumor samples were assessed for EGFR, EGFRvIII, PTEN, pAKT and pS6. Enrolled patients were heavily pre-treated including 53% who had received three or more prior chemotherapy agents and 28% who had received prior bevacizumab therapy. The most common grade > or = 2 adverse events were rash (59%), mucositis (34%) and diarrhea (31%). Grade 3 or higher events were rare. Best radiographic response included stable disease in 15 patients (47%); no patients achieved either a CR or PR. The estimated 6-month progression-free survival was 3.1% for all patients. Progression-free survival was better for patients not on EIAEDs (P = 0.03). Tumor markers failed to show an association with PFS except for increased pAKT expression which achieved borderline significance (P = 0.045). Although neither rash nor diarrhea had an association with outcome, hyperlipidemia was associated with longer PFS (P = 0.029). Erlotinib plus sirolimus was well tolerated but had negligible activity among unselected recurrent GBM patients. (ClinicalTrials.gov number: NCT0062243).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Herndon, JE; Marcello, J; Norfleet, JA; McLendon, RE; Sampson, JH; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Herndon, JE, Marcello, J, Norfleet, JA, McLendon, RE, Sampson, JH, and Friedman, HS. "Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma." J Neurooncol 96.2 (January 2010): 219-230.
PMID
19562254
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
96
Issue
2
Publish Date
2010
Start Page
219
End Page
230
DOI
10.1007/s11060-009-9950-0

Clinical applications of a peptide-based vaccine for glioblastoma.

Glioblastoma multiforme is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient's own immune system to destroy tumor cells. The most successful immunologically based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system, and reviews treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines.

Authors
Kanaly, CW; Ding, D; Heimberger, AB; Sampson, JH
MLA Citation
Kanaly, CW, Ding, D, Heimberger, AB, and Sampson, JH. "Clinical applications of a peptide-based vaccine for glioblastoma." Neurosurg Clin N Am 21.1 (January 2010): 95-109. (Review)
PMID
19944970
Source
pubmed
Published In
Neurosurgery Clinics of North America
Volume
21
Issue
1
Publish Date
2010
Start Page
95
End Page
109
DOI
10.1016/j.nec.2009.09.001

Erratum: Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1 (Journal of Neuro-Oncology DOI 10.1007/s11060-009-0046-7)

Authors
Ding, D; Kanaly, CW; Bigner, DD; Cummings, TJ; II, JEH; Pastan, I; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Bigner, DD, Cummings, TJ, II, JEH, Pastan, I, Raghavan, R, and Sampson, JH. "Erratum: Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1 (Journal of Neuro-Oncology DOI 10.1007/s11060-009-0046-7)." Journal of Neuro-Oncology 98.1 (2010): 9--.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
98
Issue
1
Publish Date
2010
Start Page
9-
DOI
10.1007/s11060-010-0183-z

Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma

Convection-enhanced delivery (CED) of cintredekin besudotox (CB) was compared with Gliadel wafers (GW) in adult patients with glioblastoma multiforme (GBM) at first recurrence. Patients were randomized 2:1 to receive CB or GW. CB (0.5 μg/mL; total flow rate 0.75 mL/h) was administered over 96 hours via 2-4 intraparenchymal catheters placed after tumor resection. GW (3.85%/7.7 mg carmustine per wafer; maximum 8 wafers) were placed immediately after tumor resection. The primary endpoint was overall survival from the time of randomization. Prestated interim analyses were built into the study design. Secondary and tertiary endpoints were safety and health-related quality-of-life assessments. From March 2004 to December 2005, 296 patients were enrolled at 52 centers. Demographic and baseline characteristics were balanced between the 2 treatment arms. Median survival was 36.4 weeks (9.1 months) for CB and 35.3 weeks (8.8 months) for GW (P = .476). For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P = .310). The adverse-events profile was similar in both arms, except that pulmonary embolism was higher in the CB arm (8% vs 1%, P = .014). This is the first randomized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics. © The Author(s) 2010.

Authors
Kunwar, S; Chang, S; Westphal, M; Vogelbaum, M; Sampson, J; Barnett, G; Shaffrey, M; Ram, Z; Piepmeier, J; Prados, M; Croteau, D; Pedain, C; Leland, P; Husain, SR; Joshi, BH; Puri, RK
MLA Citation
Kunwar, S, Chang, S, Westphal, M, Vogelbaum, M, Sampson, J, Barnett, G, Shaffrey, M, Ram, Z, Piepmeier, J, Prados, M, Croteau, D, Pedain, C, Leland, P, Husain, SR, Joshi, BH, and Puri, RK. "Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma." Neuro-Oncology 12.8 (2010): 871-881.
Source
scival
Published In
Neuro-Oncology
Volume
12
Issue
8
Publish Date
2010
Start Page
871
End Page
881
DOI
10.1093/neuonc/nop054

Convection-enhanced drug delivery to the brain

Convection-enhanced delivery (CED) is a method of direct intracerebral parenchymal infusion. It has been previously studied as a mechanism of drug delivery in glioma therapy, which is the focus of this review, and much work has gone into the utilization of this technique. CED can be modeled using several equations that describe the transport of fluid into porous tissue. More practically, variability in CED catheters has been studied and catheters are currently being designed to optimize drug delivery. While CED is a theoretically excellent way to bypass the blood-brain barrier (BBB), limitations of current approaches include excessive backflow along the catheter tract and leakage into subarachnoid and intraventricular spaces. Several drugs, including many recombinant cytotoxins, have been assessed for safety and efficacy in phase I and II clinical trials while many more are still in early preclinical stages. While drug development is important, we must also be able to assess the infusate's volume of distribution to verify adequate coverage of the target area. This can be evaluated through a number of different MRI sequencing techniques, or by co-infusing gadolinium as a tracer in a variety of different formulations, or even via software programs that can predict target distributions. This review summarizes the important advances that have been made to optimize the unique ability of CED to locally deliver high doses of powerful chemotherapeutics to gliomas for maximal tumor killing with minimal neurologic and systemic side effects. © 2010 Humana Press, a part of Springer Science+Business Media, LLC.

Authors
Ding, D; Kanaly, CW; Brady, ML; Mittermeyer, S; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Brady, ML, Mittermeyer, S, Raghavan, R, and Sampson, JH. "Convection-enhanced drug delivery to the brain." Neuromethods 45 (2010): 291-318.
Source
scival
Published In
Neuromethods
Volume
45
Publish Date
2010
Start Page
291
End Page
318
DOI
10.1007/978-1-60761-529-3_15

The Role of Tregs in Glioma-Mediated Immunosuppression: Potential Target for Intervention

The role of regulatory T cells (Tregs) in mediating immune suppression of anti-tumor immune responses is increasingly appreciated in patients with malignancies-especially within the malignant glioma patient population. This article discuss the role and prognostic significance of Tregs within glioma patients and delineates potential approaches for their inhibition that can be used alone or in combination with other immune therapeutics in clinical trials and in the clinical settings of recurrent or residual disease. © 2010 Elsevier Inc. All rights reserved.

Authors
Humphries, W; Wei, J; Sampson, JH; Heimberger, AB
MLA Citation
Humphries, W, Wei, J, Sampson, JH, and Heimberger, AB. "The Role of Tregs in Glioma-Mediated Immunosuppression: Potential Target for Intervention." Neurosurgery Clinics of North America 21.1 (2010): 125-137.
PMID
19944972
Source
scival
Published In
Neurosurgery Clinics of North America
Volume
21
Issue
1
Publish Date
2010
Start Page
125
End Page
137
DOI
10.1016/j.nec.2009.08.012

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, Sathornsumetee, S, McLendon, RE, Herndon, JE, Marcello, JE, Norfleet, J, Friedman, AH, Bigner, DD, and Friedman, HS. "Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study." Br J Cancer 101.12 (December 15, 2009): 1986-1994.
PMID
19920819
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
12
Publish Date
2009
Start Page
1986
End Page
1994
DOI
10.1038/sj.bjc.6605412

Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy.

This phase II trial evaluated efficacy and safety of temozolomide (TMZ) in combination with irinotecan (CPT-11) before radiotherapy in patients with newly diagnosed glioblastoma multiforme (GBM). Prior to radiotherapy, patients were treated with a maximum of three 6-week cycles of TMZ and CPT-11. Patients received TMZ at a dose of 200 mg/m(2)/day on days 1-5 and CPT-11 on days 1, 8, 22, and 29, with a dose adjustment for enzyme-inducing antiepileptic drug use. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), safety, and tumor O(6)-methylguanine-DNA methyltransferase (MGMT) expression. Of the 42 patients treated, 8 (19%) patients achieved a partial response. Median PFS and median OS were 3.1 and 13.8 months, respectively. Grade 3 or 4 AEs were documented in 36% of patients, most of which were hematologic (29%). Twenty-four percent of patients had grade 3 or 4 non-hematologic AEs, with gastrointestinal AEs being the most common (12%) Two patients died, one of intracranial hemorrhage and one of treatment-related renal failure. Low MGMT expression, compared with high MGMT expression, showed no significant difference in ORR (25 vs. 8%), median PFS (14 vs. 5 months) or OS (21 vs. 15 months). Although TMZ plus CPT-11 is at least comparable in efficacy to TMZ alone, this combination appears more toxic and poorly tolerated. The lack of correlation of activity with MGMT expression is intriguing, but needs further evaluation in subsequent trials.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy." J Neurooncol 95.3 (December 2009): 393-400.
PMID
19533023
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
95
Issue
3
Publish Date
2009
Start Page
393
End Page
400
DOI
10.1007/s11060-009-9937-x

EGFRvIII-targeted vaccination therapy of malignant glioma.

Given the highly infiltrative growth pattern of malignant glioma and the lack of specificity associated with currently available treatment regimens, alternative strategies designed to eradicate cancer cells while limiting collateral toxicity in normal tissues remain a high priority. To this end, the development of specific immunotherapies against targeted neoplastic cells represents a promising approach. The epidermal growth factor receptor class III variant (EGFRvIII), a constitutively activated mutant of the wild-type tyrosine kinase, is present in a substantial proportion of malignant gliomas and other human cancers, yet completely absent from normal tissues. This receptor variant consists of an in-frame deletion, the translation of which produces an extracellular junction with a novel glycine residue, flanked by amino acid sequences that are not typically adjacent in the normal protein. In this review, both preclinical and early clinical development of a peptide vaccine directed against this portion of the EGFRvIII antigenic domain are recapitulated. Following vaccination, our group has demonstrated potent, redirected cellular and humoral immunity against cancer cells expressing the mutant receptor without significant toxicity. Additionally, the corresponding therapeutic outcomes observed in these studies lend credence to the potential role of peptide-based vaccination strategies among emerging antitumor immunotherapies in patients with malignant glioma.

Authors
Choi, BD; Archer, GE; Mitchell, DA; Heimberger, AB; McLendon, RE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Archer, GE, Mitchell, DA, Heimberger, AB, McLendon, RE, Bigner, DD, and Sampson, JH. "EGFRvIII-targeted vaccination therapy of malignant glioma." Brain Pathol 19.4 (October 2009): 713-723. (Review)
PMID
19744042
Source
pubmed
Published In
Brain Pathology
Volume
19
Issue
4
Publish Date
2009
Start Page
713
End Page
723
DOI
10.1111/j.1750-3639.2009.00318.x

An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme.

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)-based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 x 10(7) +/- 2.9 x 10(7) SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 +/- 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.(95)), 2.5-8.8], and median survival time from vaccination was 18.7 months (C.I.(95), 14.5-25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.(95), 17.5-29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy.

Authors
Sampson, JH; Archer, GE; Mitchell, DA; Heimberger, AB; Herndon, JE; Lally-Goss, D; McGehee-Norman, S; Paolino, A; Reardon, DA; Friedman, AH; Friedman, HS; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Mitchell, DA, Heimberger, AB, Herndon, JE, Lally-Goss, D, McGehee-Norman, S, Paolino, A, Reardon, DA, Friedman, AH, Friedman, HS, and Bigner, DD. "An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme." Mol Cancer Ther 8.10 (October 2009): 2773-2779.
PMID
19825799
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
8
Issue
10
Publish Date
2009
Start Page
2773
End Page
2779
DOI
10.1158/1535-7163.MCT-09-0124

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma." Neuro Oncol 11.5 (October 2009): 556-561.
PMID
19289491
Source
pubmed
Published In
Neuro-Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
556
End Page
561
DOI
10.1215/15228517-2009-007

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.

INTRODUCTION: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting (211)At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. METHODS: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. RESULTS: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups. CONCLUSION: Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

Authors
Boskovitz, A; McLendon, RE; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, McLendon, RE, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab." Nucl Med Biol 36.6 (August 2009): 659-669.
PMID
19647172
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
659
End Page
669
DOI
10.1016/j.nucmedbio.2009.04.003

Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma.

BACKGROUND: The current study was a phase 1 clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG). The trial was designed to determine the maximum tolerated dose (MTD) and toxicity of irinotecan (CPT-11) when administered with temozolomide (TMZ) and O(6)-benzylguanine (O(6)-BG). METHODS: All 3 drugs, CPT-11, TMZ, and O(6)-BG, were administered on Day 1 of a 21-day treatment. First, patients were treated with a 1-hour bolus infusion of O(6)-BG at a dose of 120 mg/m(2) followed immediately by a 48-hour continuous infusion of O(6)-BG at a dose of 30 mg/m(2)/d. Second, within 60 minutes of the end of the 1-hour bolus infusion of O(6)-BG, TMZ was administered orally at a dose of 355 mg/m(2). Third, 1 hour after administration of TMZ, CPT-11 was infused over 90 minutes. Patients were accrued to 1 of 2 strata based on CYP3A1- and CYP3A4-inducing antiepileptic drug (EIAED) use; dose escalation was conducted independently within these strata. RESULTS: Fifty-five patients were enrolled. In both strata, the dose-limiting toxicities were hematologic and included grade 4 neutropenia, febrile neutropenia, leukopenia, and/or thrombocytopenia. For Stratum 1 (EIAEDs), when TMZ was administered at a dose of 355 mg/m(2), the MTD of CPT-11 was determined to be 120 mg/m(2). In contrast, for Stratum 2 (no EIAEDs), when TMZ was administered at a dose of 200 mg/m(2), the MTD of CPT-11 was determined to be 80 mg/m(2). CONCLUSIONS: The authors believe that the results of the current study provide the foundation for a phase 2 trial of O(6)-BG in combination with CPT-11 and TMZ in patients with MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, and Friedman, HS. "Phase 1 trial of temozolomide plus irinotecan plus O6-benzylguanine in adults with recurrent malignant glioma." Cancer 115.13 (July 1, 2009): 2964-2970.
PMID
19402172
Source
pubmed
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2964
End Page
2970
DOI
10.1002/cncr.24336

Toward effective immunotherapy for the treatment of malignant brain tumors.

The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.

Authors
Mitchell, DA; Sampson, JH
MLA Citation
Mitchell, DA, and Sampson, JH. "Toward effective immunotherapy for the treatment of malignant brain tumors." Neurotherapeutics 6.3 (July 2009): 527-538. (Review)
PMID
19560742
Source
pubmed
Published In
Neurotherapeutics
Volume
6
Issue
3
Publish Date
2009
Start Page
527
End Page
538
DOI
10.1016/j.nurt.2009.04.003

Paraganglioma of the head and neck: long-term local control with radiotherapy.

OBJECTIVES: Paragangliomas are rare neuroendocrine neoplasms of the head and neck. Treatment strategies include resection, definitive external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), or observation alone. Due to their rarity and indolent clinical behavior, the optimal management for long-term control is unknown. METHODS: This Institutional Review Board-approved retrospective study identified all paragangliomas of the head and neck treated with definitive fractionated radiotherapy at Duke University Medical Center from 1963 to 2005 with minimum 2-year follow-up. Local control (LC) was calculated using the Kaplan-Meier method. RESULTS: Thirty-one patients were identified and treated with EBRT (median dose: 54 Gy, range: 38-65 Gy). Twelve patients were treated with megavoltage photon; 19 were treated with either cobalt-60 or cesium-137. Fourteen (45%) had undergone resection preceding radiation. Median follow-up was 9 years (range: 2-35 years), with 10 patients having greater than 15-year follow-up. LC at 5, 10, and 15 years was 96%, 90%, and 90%, respectively. There were no failures in the group treated with megavoltage photons, although this was not statistically significant (P = 0.28). There was no difference in LC between salvage radiation therapy (RT) used after surgical failure and definitive RT alone (10-year LC, 73% vs. 100%, respectively, P = 0.31). The incidence of acute toxicity greater than grade 2 was 3%, and there were no late toxicities greater than grade 2. CONCLUSIONS: RT is an effective and well-tolerated treatment for paragangliomas of the head and neck.

Authors
Chino, JP; Sampson, JH; Tucci, DL; Brizel, DM; Kirkpatrick, JP
MLA Citation
Chino, JP, Sampson, JH, Tucci, DL, Brizel, DM, and Kirkpatrick, JP. "Paraganglioma of the head and neck: long-term local control with radiotherapy." Am J Clin Oncol 32.3 (June 2009): 304-307.
PMID
19433962
Source
pubmed
Published In
American Journal of Clinical Oncology: Cancer Clinical Trials
Volume
32
Issue
3
Publish Date
2009
Start Page
304
End Page
307
DOI
10.1097/COC.0b013e318187dd94

A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas.

Previous studies have shown that neurokinin 1 receptor (NK1R) occurs naturally in human glioblastomas and its stimulation causes cell proliferation. In the present study we show that stimulation of NK1R in human U373 glioblastoma cells by substance P increases Akt phosphorylation by 2.5-fold, with an EC(50) of 57 nM. Blockade of NK1R lowers basal phosphorylation of Akt, indicating the presence of a constitutively active form of NK1R; similar results are seen in U251 MG and DBTRG-05 glioblastoma cells. Linkage of NK1R to Akt implicates NK1R in apoptosis of glioblastoma cells. Indeed, treatment of serum-starved U373 cells with substance P reduces apoptosis by 53 +/- 1% (p < 0.05), and treatment with NK1R antagonist L-733,060 increases apoptosis by 64 +/- 16% (p < 0.01). Further, the blockade of NK1R in human glioblastoma cells with L-733,060 causes cleavage of Caspase-3 and proteolysis of poly (ADP-ribose) polymerase. Experiments designed to elucidate the mechanism of NK1R-mediated Akt phosphorylation revealed total involvement of non-receptor tyrosine kinase Src and phosphatidyl-3-kinase, a partial involvement of epidermal growth factor receptor, and no involvement of mitogen-activated protein/extracellular signal-related kinase. Taken together, the results of the present study indicate a key role for NK1R in glioblastoma apoptosis.

Authors
Akazawa, T; Kwatra, SG; Goldsmith, LE; Richardson, MD; Cox, EA; Sampson, JH; Kwatra, MM
MLA Citation
Akazawa, T, Kwatra, SG, Goldsmith, LE, Richardson, MD, Cox, EA, Sampson, JH, and Kwatra, MM. "A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas." J Neurochem 109.4 (May 2009): 1079-1086.
PMID
19519779
Source
pubmed
Published In
Journal of Neurochemistry
Volume
109
Issue
4
Publish Date
2009
Start Page
1079
End Page
1086
DOI
10.1111/j.1471-4159.2009.06032.x

Proteomic and immunologic analyses of brain tumor exosomes.

Brain tumors are horrific diseases with almost universally fatal outcomes; new therapeutics are desperately needed and will come from improved understandings of glioma biology. Exosomes are endosomally derived 30-100 nm membranous vesicles released from many cell types into the extracellular milieu; surprisingly, exosomes are virtually unstudied in neuro-oncology. These microvesicles were used as vaccines in other tumor settings, but their immunological significance is unevaluated in brain tumors. Our purpose here is to report the initial biochemical, proteomic, and immunological studies on murine brain tumor exosomes, following known procedures to isolate exosomes. Our findings show that these vesicles have biophysical characteristics and proteomic profiles similar to exosomes from other cell types but that brain tumor exosomes have unique features (e.g., very basic isoelectric points, expressing the mutated tumor antigen EGFRvIII and the putatively immunosuppressive cytokine TGF-beta). Administration of such exosomes into syngeneic animals produced both humoral and cellular immune responses in immunized hosts capable of rejecting subsequent tumor challenges but failed to prolong survival in established orthotopic models. Control animals received saline or cell lysate vaccines and showed no antitumor responses. Exosomes and microvesicles isolated from sera of patients with brain tumors also possess EGFR, EGFRvIII, and TGF-beta. We conclude that exosomes released from brain tumor cells are biochemically/biophysically like other exosomes and have immune-modulating properties. They can escape the blood-brain barrier, with potential systemic and distal signaling and immune consequences.

Authors
Graner, MW; Alzate, O; Dechkovskaia, AM; Keene, JD; Sampson, JH; Mitchell, DA; Bigner, DD
MLA Citation
Graner, MW, Alzate, O, Dechkovskaia, AM, Keene, JD, Sampson, JH, Mitchell, DA, and Bigner, DD. "Proteomic and immunologic analyses of brain tumor exosomes." FASEB J 23.5 (May 2009): 1541-1557.
PMID
19109410
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
23
Issue
5
Publish Date
2009
Start Page
1541
End Page
1557
DOI
10.1096/fj.08-122184

RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma

Authors
Mitchell, DA; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; Perry, B; II, HJE; McGehee, S; McLendon, RE; Reardon, D; Sampson, JH
MLA Citation
Mitchell, DA, Archer, GE, Bigner, DD, Friedman, HS, Lally-Goss, D, Perry, B, II, HJE, McGehee, S, McLendon, RE, Reardon, D, and Sampson, JH. "RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma." May 2009.
Source
wos-lite
Published In
Molecular Therapy
Volume
17
Publish Date
2009
Start Page
S93
End Page
S93

Stereotactic body radiotherapy for lesions of the spine and paraspinal regions.

PURPOSE: To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions. METHODS AND MATERIALS: Thirty-two patients with 33 spinal lesions underwent computed tomography-based simulation while free breathing. Gross/clinical target volumes included involved portions of the vertebral body and paravertebral/epidural tumor. Planning target volume (PTV) expansion was 6 mm axially and 3 mm radially; the cord was excluded from the PTV. Biologic equivalent dose was calculated using the linear quadratic model with alpha/beta = 3 Gy. Treatment was linear accelerator based with on-board imaging; dose was adjusted to maintain cord dose within tolerance. Survival, local control, pain, and neurologic status were monitored. RESULTS: Twenty-one patients are alive at 1 year (median survival, 14 months). Median follow-up is 6 months for all patients (7 months for survivors). Mean previous radiotherapy dose to 22 patients was 35 Gy, and median interval was 17 months. Renal (31%), breast, and lung (19% each) were the most common histologic sites. Three SBRT fractions (range, one to four fractions) of 7 Gy (range, 5-16 Gy) were delivered. Median cord and target biologic equivalent doses were 70 Gy(3) and 34.3 Gy(10), respectively. Thirteen patients reported complete and 17 patients reported partial pain relief at 1 month. There were four failures (mean, 5.8 months) with magnetic resonance imaging evidence of in-field progression. No dosimetric parameters predictive of failure were identified. No treatment-related toxicity was seen. CONCLUSIONS: Spinal SBRT is effective in the palliative/re-treatment setting. Volume expansion must ensure optimal PTV coverage while avoiding spinal cord toxicity. The long-term safety of spinal SBRT and the applicability of the linear-quadratic model in this setting remain to be determined, particularly the time-adjusted impact of prior radiotherapy.

Authors
Nelson, JW; Yoo, DS; Sampson, JH; Isaacs, RE; Larrier, NA; Marks, LB; Yin, F-F; Wu, QJ; Wang, Z; Kirkpatrick, JP
MLA Citation
Nelson, JW, Yoo, DS, Sampson, JH, Isaacs, RE, Larrier, NA, Marks, LB, Yin, F-F, Wu, QJ, Wang, Z, and Kirkpatrick, JP. "Stereotactic body radiotherapy for lesions of the spine and paraspinal regions." Int J Radiat Oncol Biol Phys 73.5 (April 1, 2009): 1369-1375.
PMID
19004569
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
73
Issue
5
Publish Date
2009
Start Page
1369
End Page
1375
DOI
10.1016/j.ijrobp.2008.06.1949

INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM

Authors
Archer, GE; Heimberger, AB; Bigner, DD; Davis, T; Friedman, HS; Keler, T; McLendon, RE; Mitchell, DA; Reardon, D; Sawaya, R; Vredenberg, J; Sampson, JH
MLA Citation
Archer, GE, Heimberger, AB, Bigner, DD, Davis, T, Friedman, HS, Keler, T, McLendon, RE, Mitchell, DA, Reardon, D, Sawaya, R, Vredenberg, J, and Sampson, JH. "INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

THE RNA-BINDING PROTEIN 76 CONTROLS GENE EXPRESSION IN GBM

Authors
Gromeier, M; Neplioueva, V; Makherjee, N; Merrill, M; Sampson, JH
MLA Citation
Gromeier, M, Neplioueva, V, Makherjee, N, Merrill, M, and Sampson, JH. "THE RNA-BINDING PROTEIN 76 CONTROLS GENE EXPRESSION IN GBM." NEURO-ONCOLOGY 11.2 (April 2009): 221-221.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
221
End Page
221

Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

PURPOSE: This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide. PATIENTS AND METHODS: Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. RESULTS: Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. CONCLUSION: O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma." J Clin Oncol 27.8 (March 10, 2009): 1262-1267.
PMID
19204199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
8
Publish Date
2009
Start Page
1262
End Page
1267
DOI
10.1200/JCO.2008.18.8417

Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

PURPOSE: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. EXPERIMENTAL DESIGN: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. RESULTS: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%). CONCLUSION: The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

Authors
Quinn, JA; Jiang, SX; Carter, J; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Threatt, S; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Carter, J, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Threatt, S, and Friedman, HS. "Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme." Clin Cancer Res 15.3 (February 1, 2009): 1064-1068.
PMID
19188181
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
3
Publish Date
2009
Start Page
1064
End Page
1068
DOI
10.1158/1078-0432.CCR-08-2130

The role of tregs in human glioma patients and their inhibition with a novel STAT-3 inhibitor

Authors
Heimberger, AB; Kong, L-Y; Abou-Ghazal, M; Reina-Ortiz, C; Yang, DS; Wei, J; Wei, Q; Schmittling, RJ; Archer, GE; Sampson, JH; Hiraoka, N; Priebe, W; Fuller, GN; Sawaya, R
MLA Citation
Heimberger, AB, Kong, L-Y, Abou-Ghazal, M, Reina-Ortiz, C, Yang, DS, Wei, J, Wei, Q, Schmittling, RJ, Archer, GE, Sampson, JH, Hiraoka, N, Priebe, W, Fuller, GN, and Sawaya, R. "The role of tregs in human glioma patients and their inhibition with a novel STAT-3 inhibitor." Clinical Neurosurgery 56 (2009): 98-106.
PMID
20214040
Source
scival
Published In
Clinical neurosurgery
Volume
56
Publish Date
2009
Start Page
98
End Page
106

Anatomic compression caused by high-volume convection-enhanced delivery to the brain: Commentary

Authors
Sampson, JH
MLA Citation
Sampson, JH. "Anatomic compression caused by high-volume convection-enhanced delivery to the brain: Commentary." Neurosurgery 65.3 (2009): 585-586.
Source
scival
Published In
Neurosurgery
Volume
65
Issue
3
Publish Date
2009
Start Page
585
End Page
586
DOI
10.1227/01.NEU.0000350229.77462.2F

The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, resulting in non-specific toxicity. Immune targeting of tumor-specific mutations may allow for more precise eradication of neoplastic cells. EGFR variant III (EGFRvIII) is a tumor-specific mutation that is widely expressed in GBM and other neoplasms and its expression enhances tumorigenicity. This in-frame deletion mutation splits a codon, resulting in a novel glycine at the fusion junction producing a tumor-specific epitope target for cellular or humoral immunotherapy. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction (PEPvIII-KLH/CDX-110) is an efficacious immunotherapy in syngeneic murine models. In this review, we summarize our results in GBM patients targeting this mutation in multiple, multi-institutional Phase II immunotherapy trials. These trials demonstrated that a selected population of GBM patients who received vaccines targeting EGFRvIII had an unexpectedly long survival time. Further therapeutic strategies and potential pitfalls of using this approach are discussed. © 2009 Informa UK Ltd. All rights reserved.

Authors
Heimberger, AB; Sampson, JH
MLA Citation
Heimberger, AB, and Sampson, JH. "The PEPvIII-KLH (CDX-110) vaccine in glioblastoma multiforme patients." Expert Opinion on Biological Therapy 9.8 (2009): 1087-1098.
PMID
19591631
Source
scival
Published In
Expert Opinion on Biological Therapy
Volume
9
Issue
8
Publish Date
2009
Start Page
1087
End Page
1098
DOI
10.1517/14712590903124346

IgE, allergy, and risk of glioma: Update from the San Francisco Bay Area Adult Glioma Study in the Temozolomide era

The consistently observed inverse relationship of allergic conditions with glioma risk and our previous demonstration that immunoglobulin E (IgE) levels also were lower in glioma patients than controls suggest that atopic allergy may be related to a mechanism that inhibits or prevents glioma. We sought to extend these results with a new and larger series of patients (n 5 535 with questionnaire data; 393 with IgE measures) and controls (n 5 532 with questionnaire data; 470 with IgE measures). As expected, glioma cases were less likely than controls to report history of allergies [among self-reported cases, Odds ratios (OR) 5 0.59, 95% confi-dence interval (CI): 0.41-0.85]. IgE levels also were lower in glioma cases versus controls (OR per unit log IgE 5 0.89, 95% CI (0.82-0.98). However, this inverse relationship was only apparent among cases receiving temozolomide, a treatment which became part of the "standard of care" for glioblastoma patients during the study period. Among patients receiving temozolomide, IgE levels in cases whose blood samples were obtained within 30 days of diagnosis were slightly higher than controls, whereas IgE levels in cases whose blood sample was obtained >60 days after diagnosis were significantly lower than controls (OR 5 0.80; 95% CI: 0.71-0.89). Thus, although our results robustly confirm the inverse association between allergy and glioma, the results for IgE are affected by temozolomide treatments which may have influenced IgE levels. These results have implications for the study of immunologic factors in glioma as well as for immunotherapy protocols for treating glioma. © 2009 UICC.

Authors
Wiemels, JL; Wilson, D; Patil, C; Patoka, J; McCoy, L; Rice, T; Schwartzbaum, J; Heimberger, A; Sampson, JH; Chang, S; Prados, M; Wiencke, JK; Wrensch, M
MLA Citation
Wiemels, JL, Wilson, D, Patil, C, Patoka, J, McCoy, L, Rice, T, Schwartzbaum, J, Heimberger, A, Sampson, JH, Chang, S, Prados, M, Wiencke, JK, and Wrensch, M. "IgE, allergy, and risk of glioma: Update from the San Francisco Bay Area Adult Glioma Study in the Temozolomide era." International Journal of Cancer 125.3 (2009): 680-687.
PMID
19408307
Source
scival
Published In
International Journal of Cancer
Volume
125
Issue
3
Publish Date
2009
Start Page
680
End Page
687
DOI
10.1002/ijc.24369

Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines.

The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in glioblastoma multiforme (GBM) and other neoplasms. As such it represents a truly tumor-specific target for antitumor immunotherapy. Although endogenous humoral responses to EGFRvIII have been reported in patients with EGFRvIII-expressing breast cancer, it is not known whether de novo responses can be generated or endogenous responses enhanced with an EGFRvIII-specific vaccine. To assess this in clinical trials, we have developed and validated an immunoassay to measure and isolate anti-EGFRvIII and anti-KLH antibodies from the serum of patients vaccinated with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH). Using magnetic beads with immobilized antigen we captured and detected anti-EGFRvIII and anti-KLH antibodies in serum from patients before and after vaccinations. Using this assay, we found that significant levels of antibody for tumor-specific antigen EGFRvIII (>4 microg/mL) and KLH could be induced after vaccination with PEPvIII-KLH.

Authors
Schmittling, RJ; Archer, GE; Mitchell, DA; Heimberger, A; Pegram, C; Herndon, JE; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Schmittling, RJ, Archer, GE, Mitchell, DA, Heimberger, A, Pegram, C, Herndon, JE, Friedman, HS, Bigner, DD, and Sampson, JH. "Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines." J Immunol Methods 339.1 (November 30, 2008): 74-81.
PMID
18775433
Source
pubmed
Published In
Journal of Immunological Methods
Volume
339
Issue
1
Publish Date
2008
Start Page
74
End Page
81
DOI
10.1016/j.jim.2008.08.004

Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas.

PURPOSE: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. EXPERIMENTAL DESIGN: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. RESULTS: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. CONCLUSION: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Authors
Desjardins, A; Reardon, DA; Herndon, JE; Marcello, J; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, Herndon, JE, Marcello, J, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Bailey, L, Bigner, DD, Friedman, AH, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas." Clin Cancer Res 14.21 (November 1, 2008): 7068-7073.
PMID
18981004
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
21
Publish Date
2008
Start Page
7068
End Page
7073
DOI
10.1158/1078-0432.CCR-08-0260

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma.

Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence re-arrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and lead to an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens.

Authors
Sampson, JH; Archer, GE; Mitchell, DA; Heimberger, AB; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Mitchell, DA, Heimberger, AB, and Bigner, DD. "Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma." Semin Immunol 20.5 (October 2008): 267-275. (Review)
PMID
18539480
Source
pubmed
Published In
Seminars in Immunology
Volume
20
Issue
5
Publish Date
2008
Start Page
267
End Page
275
DOI
10.1016/j.smim.2008.04.001

Cryptococcal meningitis in patients with glioma: a report of two cases.

OBJECTIVE AND IMPORTANCE: We describe two patients with high-grade glioma undergoing treatment with corticosteroids and chemotherapy who presented with cryptococcal meningitis and sepsis. This report of two cases highlights the importance of examining the efficacy of prophylactic antibiotic and/or antifungal regimens in this patient population due to their increased risk of opportunistic infections. CLINICAL PRESENTATION: A 73-year-old man with a history of glioblastoma multiforme (GBM), on dexamethasone and status post radiation therapy and two cycles of temozolamide, presented with decreased level of consciousness for 24 h and was found to have cerebrospinal fluid (CSF) and blood cultures positive for Cryptococcus neoformans. A 33-year-old man with a history of anaplastic astrocytoma, on dexamethasone and status post radiation therapy, four cycles of temozolomide and two cycles of Lomustine (CCNU), presented with headache, dizziness and photophobia and was found to have CSF and blood cultures positive for Cryptococcus neoformans. INTERVENTION: Both patients were treated with an initial regimen of amphotericin B and flucytosine for a minimum of two weeks and switched to fluconazole for 6 months to 1 year of treatment. CONCLUSION: Patients with high-grade glioma treated with long-term corticosteroid therapy and chemotherapy are at increased risk of developing opportunistic infections. The two patients reported here developed cryptococcal meningitis and sepsis. Prophylactic regimens with either fluconazole or itraconazole currently exist that effectively decrease the incidence of both cryptococcal infections. Further investigations into the risk:benefit ratio of primary prophylactic therapy in this patient population may prove beneficial.

Authors
Choi, JD; Powers, CJ; Vredenburgh, JJ; Friedman, AH; Sampson, JH
MLA Citation
Choi, JD, Powers, CJ, Vredenburgh, JJ, Friedman, AH, and Sampson, JH. "Cryptococcal meningitis in patients with glioma: a report of two cases." J Neurooncol 89.1 (August 2008): 51-53.
PMID
18398572
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
89
Issue
1
Publish Date
2008
Start Page
51
End Page
53
DOI
10.1007/s11060-008-9581-x

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses

Authors
Sampson, JH; Akabani, G; Archer, GE; Berger, MS; Coleman, RE; Friedman, AH; Friedman, HS; Greer, K; Herndon, JE; Kunwar, S; McLendon, RE; Paolino, A; Petry, NA; Provenzale, JM; Reardon, DA; Wong, TZ; Zalutsky, MR; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Berger, MS, Coleman, RE, Friedman, AH, Friedman, HS, Greer, K, Herndon, JE, Kunwar, S, McLendon, RE, Paolino, A, Petry, NA, Provenzale, JM, Reardon, DA, Wong, TZ, Zalutsky, MR, Pastan, I, and Bigner, DD. "Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors." Neuro Oncol 10.3 (June 2008): 320-329.
PMID
18403491
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
320
End Page
329
DOI
10.1215/15228517-2008-012

Combating immunosuppression in glioma.

Despite maximal therapy, malignant gliomas have a very poor prognosis. Patients with glioma express significant immune defects, including CD4 lymphopenia, increased fractions of regulatory T cells in peripheral blood and shifts in cytokine profiles from Th1 to Th2. Recent studies have focused on ways to combat immunosuppression in patients with glioma as well as in animal models for glioma. We concentrate on two specific ways to combat immunosuppression: inhibition of TGF-beta signaling and modulation of regulatory T cells. TGF-beta signaling can be interrupted by antisense oligonucleotide technology, TGF-beta receptor I kinase inhibitors, soluble TGF-beta receptors and antibodies against TGF-beta. Regulatory T cells have been targeted with antibodies against T-cell markers, such as CD25, CTLA-4 and GITR. In addition, vaccination against Foxp3 has been explored. The results of these studies have been encouraging; combating immunosuppression may be one key to improving prognosis in malignant glioma.

Authors
Vega, EA; Graner, MW; Sampson, JH
MLA Citation
Vega, EA, Graner, MW, and Sampson, JH. "Combating immunosuppression in glioma." Future oncology (London, England) 4.3 (June 2008): 433-442. (Review)
PMID
18518768
Source
epmc
Published In
Future oncology (London, England)
Volume
4
Issue
3
Publish Date
2008
Start Page
433
End Page
442
DOI
10.2217/14796694.4.3.433

Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma.

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines.

Authors
Everson, RG; Graner, MW; Gromeier, M; Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Everson, RG, Graner, MW, Gromeier, M, Vredenburgh, JJ, Desjardins, A, Reardon, DA, Friedman, HS, Friedman, AH, Bigner, DD, and Sampson, JH. "Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma." Expert Rev Anticancer Ther 8.5 (May 2008): 717-732. (Review)
PMID
18471045
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
8
Issue
5
Publish Date
2008
Start Page
717
End Page
732
DOI
10.1586/14737140.8.5.717

Selective modification of antigen-specific T cells by RNA electroporation.

It has been observed that the efficient transfection of T cells by RNA electroporation requires prior activation of T cells with mitogens or by anti-CD3 antibody stimulation. We hypothesized that this requirement for T cell activation could be leveraged to express marker genes within activated T cells responding to antigen-pulsed dendritic cells and allow for the selective enrichment and modification of antigen-specific T cells. Using electroporation of mRNA encoding green fluorescent protein as a marker gene, we demonstrate that RNA electroporation can efficiently allow for the separation of cytomegalovirus-specific CD8+ and CD4+ T cells from bulk culture responding to cytomegalovirus pp65 antigen-pulsed dendritic cells. Furthermore, we demonstrate that cytomegalovirus-specific T cells can be functionally modified by RNA transfection of the C-X-C chemokine receptor, CXCR2, to migrate efficiently toward a variety of CXCR2-specific chemokines in vitro and in vivo. These studies demonstrate the utility of RNA transfection as a simple method by which to purify and selectively modify the function of antigen-specific T cells for use in adoptive immunotherapy, and importantly provide evidence that transient expression of proteins by RNA transfection is an efficient means of modulating the in vivo function of activated T cells.

Authors
Mitchell, DA; Karikari, I; Cui, X; Xie, W; Schmittling, R; Sampson, JH
MLA Citation
Mitchell, DA, Karikari, I, Cui, X, Xie, W, Schmittling, R, and Sampson, JH. "Selective modification of antigen-specific T cells by RNA electroporation." Human gene therapy 19.5 (May 2008): 511-521.
PMID
18471037
Source
epmc
Published In
Human Gene Therapy
Volume
19
Issue
5
Publish Date
2008
Start Page
511
End Page
521
DOI
10.1089/hum.2007.115

Molecular strategies for the treatment of malignant glioma--genes, viruses, and vaccines.

The standard treatment paradigm of surgery, radiation, and chemotherapy for malignant gliomas has only a modest effect on survival. It is well emphasized in the literature that despite aggressive multimodal therapy, most patients survive approximately 1 year after diagnosis, and less than 10% survive beyond 2 years. This dismal prognosis provides the impetus for ongoing investigations in search of improved therapeutics. Standard multimodal therapy has largely reached a plateau in terms of effectiveness, and there is now a growing body of literature on novel molecular approaches for the treatment of malignant gliomas. Gene therapy, oncolytic virotherapy, and immunotherapy are the major investigational approaches that have demonstrated promise in preclinical and early clinical studies. These new molecular technologies each have distinct advantages and limitations, and none has yet demonstrated a significant survival benefit in a phase II or III clinical trial. Molecular approaches may not lead to the discovery of a "magic bullet" for these aggressive tumors, but they may ultimately prove synergistic with more conventional approaches and lead to a broadening of the multimodal approach that is the current standard of care. This review will discuss the scientific background, therapeutic potential, and clinical limitations of these novel strategies with a focus on those that have made it to clinical trials.

Authors
Selznick, LA; Shamji, MF; Fecci, P; Gromeier, M; Friedman, AH; Sampson, J
MLA Citation
Selznick, LA, Shamji, MF, Fecci, P, Gromeier, M, Friedman, AH, and Sampson, J. "Molecular strategies for the treatment of malignant glioma--genes, viruses, and vaccines." Neurosurg Rev 31.2 (April 2008): 141-155. (Review)
PMID
18259789
Source
pubmed
Published In
Neurosurgical Review
Volume
31
Issue
2
Publish Date
2008
Start Page
141
End Page
155
DOI
10.1007/s10143-008-0121-0

Immunotherapy of malignant brain tumors.

Despite aggressive multi-modality therapy including surgery, radiation, and chemotherapy, the prognosis for patients with malignant primary brain tumors remains very poor. Moreover, the non-specific nature of conventional therapy for brain tumors often results in incapacitating damage to surrounding normal brain and systemic tissues. Thus, there is an urgent need for the development of therapeutic strategies that precisely target tumor cells while minimizing collateral damage to neighboring eloquent cerebral cortex. The rationale for using the immune system to target brain tumors is based on the premise that the inherent specificity of immunologic reactivity could meet the clear need for more specific and precise therapy. The success of this modality is dependent on our ability to understand the mechanisms of immune regulation within the central nervous system (CNS), as well as counter the broad defects in host cell-mediated immunity that malignant gliomas are known to elicit. Recent advances in our understanding of tumor-induced and host-mediated immunosuppressive mechanisms, the development of effective strategies to combat these suppressive effects, and a better understanding of how to deliver immunologic effector molecules more efficiently to CNS tumors have all facilitated significant progress toward the realization of true clinical benefit from immunotherapeutic treatment of malignant gliomas.

Authors
Mitchell, DA; Fecci, PE; Sampson, JH
MLA Citation
Mitchell, DA, Fecci, PE, and Sampson, JH. "Immunotherapy of malignant brain tumors." Immunol Rev 222 (April 2008): 70-100. (Review)
PMID
18363995
Source
pubmed
Published In
Immunological Reviews
Volume
222
Publish Date
2008
Start Page
70
End Page
100
DOI
10.1111/j.1600-065X.2008.00603.x

Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma.

Human cytomegalovirus (HCMV) has been described to be associated with several human malignancies, though the frequency of detection remains controversial. It is unclear whether HCMV plays an active role in malignant tumor progression or becomes reactivated under pathologic conditions that result in chronic inflammation or immunosuppression. In this study, we report on the investigation of detecting HCMV in the tumors and peripheral blood of patients with newly diagnosed glioblastoma multiforme (GBM). Using immunohistochemistry, in situ hybridization, and polymerase chain reaction amplification of viral DNA, the detection of HCMV was investigated in tumor and blood specimens from patients with GBM as well as in the peripheral blood of normal volunteers and patients undergoing craniotomy for diagnoses other than GBM. We found that a high percentage (>90%) of GBM tumors, not surrounding normal brain, are associated with HCMV nucleic acids and proteins. Furthermore, a significant proportion of patients (80%) with newly diagnosed GBM have detectable HCMV DNA in their peripheral blood, while sero-positive normal donors and other surgical patients did not exhibit detectable virus, suggesting either a systemic reactivation of HCMV within patients with GBM or shedding of viral DNA from infected tumor cells into the periphery. These results confirm the association of HCMV with malignant gliomas and demonstrate that subclinical HCMV viremia (presence of viral DNA in blood without clinical symptoms of infection) is a previously unrecognized disease spectrum in patients with GBM.

Authors
Mitchell, DA; Xie, W; Schmittling, R; Learn, C; Friedman, A; McLendon, RE; Sampson, JH
MLA Citation
Mitchell, DA, Xie, W, Schmittling, R, Learn, C, Friedman, A, McLendon, RE, and Sampson, JH. "Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma." Neuro Oncol 10.1 (February 2008): 10-18.
PMID
17951512
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
1
Publish Date
2008
Start Page
10
End Page
18
DOI
10.1215/15228517-2007-035

Cholesterol granuloma of the lateral ventricle. Case report.

Cholesterol granulomas (CGs) are benign lesions resulting from an inflammatory reaction to cholesterol and hemosiderin. These masses most often arise within the temporal bone or nasal sinuses; intracerebral CGs are extremely rare. In this report the authors present an unusual case of a CG arising within the lateral ventricle. The patient presented with transient hemiparesis and numbness. Computed tomography and magnetic resonance imaging demonstrated a cystic partially enhancing midline mass within the right lateral ventricle, expanding the ventricle and displacing the septum pellucidum. The patient underwent an interhemispheric, transcallosal resection of the lesion. Microscopic examination revealed a granulomatous inflammatory lesion containing cholesterol clefts, macrophages, and hemosiderin. Embedded within the granulomatous response were foci of tiny cystlike structures lined by nonciliated flattened cuboidal epithelium, consistent with the diagnosis of CG. To the authors' knowledge this is the first reported case of CG presenting as an intraventricular mass. The origin of this lesion is unclear, but it may relate to prior traumatic brain injury. The authors describe the presentation, imaging findings, histopathological characteristics, and surgical treatment of this rare lesion and related pathological entities.

Authors
Grossi, PM; Ellis, MJ; Cummings, TJ; Gray, LL; Fukushima, T; Sampson, JH
MLA Citation
Grossi, PM, Ellis, MJ, Cummings, TJ, Gray, LL, Fukushima, T, and Sampson, JH. "Cholesterol granuloma of the lateral ventricle. Case report." J Neurosurg 108.2 (February 2008): 357-360.
PMID
18240934
Source
pubmed
Published In
Journal of neurosurgery
Volume
108
Issue
2
Publish Date
2008
Start Page
357
End Page
360
DOI
10.3171/JNS/2008/108/2/0357

Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study.

Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemotherapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery.

Authors
Heimberger, AB; Sun, W; Hussain, SF; Dey, M; Crutcher, L; Aldape, K; Gilbert, M; Hassenbusch, SJ; Sawaya, R; Schmittling, B; Archer, GE; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Sun, W, Hussain, SF, Dey, M, Crutcher, L, Aldape, K, Gilbert, M, Hassenbusch, SJ, Sawaya, R, Schmittling, B, Archer, GE, Mitchell, DA, Bigner, DD, and Sampson, JH. "Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study." Neuro Oncol 10.1 (February 2008): 98-103.
PMID
18079360
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
1
Publish Date
2008
Start Page
98
End Page
103
DOI
10.1215/15228517-2007-046

EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells.

PURPOSE: Immunotoxins as anti-cancer therapeutics have several potential advantages over conventional agents including a high specificity, extraordinary potency, and a lack of an identified mechanism for resistance. It has been clearly demonstrated that Pseudomonas-based immunotoxins have a direct cytotoxic effect. However, delayed and often dramatic antitumor responses seen in human studies with targeted toxins led us to hypothesize that immunologic responses may be a secondary mechanism that enhances the therapeutic efficacy of these novel drugs. EXPERIMENTAL DESIGN: This hypothesis was tested in a murine system using an immunotoxin, MR1-1 [MR1-1(dsFv)-PE38KDEL], that targets a syngeneic murine homologue of the tumor-specific human epidermal growth factor mutation, EGFRvIII, expressed on a murine cell line. RESULTS: Intratumoral treatment with MR1-1 eliminated EGFRvIII-expressing tumors (P < 0.0001). The antitumor activity of MR1-1 was dependent on the expression of EGFRvIII on some, but not all tumors cells, and was significantly inhibited in the absence of CD4+ (P = 0.0193) and CD8+ (P = 0.0193) T cells. MR1-1 induced EGFRvIII-specific immunity (P < 0.0005) and produced long lasting immunity against tumors expressing EGFRvIII as well as EGFRvIII-negative tumors. CONCLUSIONS: These data suggest that immunotoxins may not be strictly dependent on direct cytotoxicity for their efficacy, but may also be potent inducers of antitumor immunity active even against cells that do not express the targeted antigen.

Authors
Ochiai, H; Archer, GE; Herndon, JE; Kuan, C-T; Mitchell, DA; Bigner, DD; Pastan, IH; Sampson, JH
MLA Citation
Ochiai, H, Archer, GE, Herndon, JE, Kuan, C-T, Mitchell, DA, Bigner, DD, Pastan, IH, and Sampson, JH. "EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells." Cancer Immunol Immunother 57.1 (January 2008): 115-121.
PMID
17634939
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
57
Issue
1
Publish Date
2008
Start Page
115
End Page
121
DOI
10.1007/s00262-007-0363-7

A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells

Purpose: Activation of signal transducers and activators of transcription 3 (STAT3) has been identified as a central mediator of melanoma growth and metastasis. We hypothesized that WP1066, a novel STAT3 blockade agent, has marked antitumor activity, even against the melanoma metastasis to brain, a site typically refractory to therapies. Experimental Design: The antitumor activities and related mechanisms of WP1066 were investigated both in vitro on melanoma cell lines and in vivo on mice with subcutaneously syngeneic melanoma or with intracerebral melanoma tumors. Results: WP1066 achieved an IC 50 of 1.6, 2.3, and 1.5 μmol/L against melanoma cell line A375, B16, and B16EGFRvlll, respectively. WPI066 suppressed the phosphorylation of Janus-activated kinase 2 and STAT3 (Tyr705) in these cells. Tumor growth in mice with subcutaneously established syngeneic melanoma was markedly inhibited by WP1066 compared with that in controls. Long-term survival (>78 days) was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to control mice who survived for a median of 15 days. Although WP1066 did not induce immunologic memory or enhance humoral responses to EGFRvlll, this compound reduced the production of immunosuppressive cytokines and chemokines (transforming growth factor-β, RANTES, MCP-1, vascular endothelial growth factor), markedly inhibited natural and inducible Treg proliferation, and significantly increased cytotoxic immune responses of Tcells. Conclusions: The antitumor cytotoxic effects of WP1066 and its ability to induce antitumor immune responses suggest that this compound has potential for the effective treatment of melanoma metastatic to brain. © 2008 American Association for Cancer Research.

Authors
Kong, L-Y; Abou-Ghazal, MK; Wei, J; Chakraborty, A; Sun, W; Qiao, W; Fuller, GN; Fokt, I; Grimm, EA; Schmittling, RJ; Jr, GEA; Sampson, JH; Priebe, W; Heimberger, AB
MLA Citation
Kong, L-Y, Abou-Ghazal, MK, Wei, J, Chakraborty, A, Sun, W, Qiao, W, Fuller, GN, Fokt, I, Grimm, EA, Schmittling, RJ, Jr, GEA, Sampson, JH, Priebe, W, and Heimberger, AB. "A novel inhibitor of signal transducers and activators of transcription 3 activation is efficacious against established central nervous system melanoma and inhibits regulatory T cells." Clinical Cancer Research 14.18 (2008): 5759-5768.
PMID
18794085
Source
scival
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
18
Publish Date
2008
Start Page
5759
End Page
5768
DOI
10.1158/1078-0432.CCR-08-0377

Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery: Laboratory investigation

Object. The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage. Methods. The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage. Results. The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage. Conclusions. An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.

Authors
Varenika, V; Dickinson, P; Bringas, J; LeCouteur, R; Higgins, R; Park, J; Fiandaca, M; Berger, M; Sampson, J; Bankiewicz, K
MLA Citation
Varenika, V, Dickinson, P, Bringas, J, LeCouteur, R, Higgins, R, Park, J, Fiandaca, M, Berger, M, Sampson, J, and Bankiewicz, K. "Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery: Laboratory investigation." Journal of Neurosurgery 109.5 (2008): 874-880.
PMID
18976077
Source
scival
Published In
Journal of neurosurgery
Volume
109
Issue
5
Publish Date
2008
Start Page
874
End Page
880
DOI
10.3171/JNS/2008/109/11/0874

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Marcello, J; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Wagner, M; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Herndon, JE, Marcello, J, Reardon, DA, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Wagner, M, Bailey, L, Bigner, DD, Friedman, AH, and Friedman, HS. "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme." J Clin Oncol 25.30 (October 20, 2007): 4722-4729.
PMID
17947719
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2007.12.2440

Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions.

Convection-enhanced delivery (CED) is a novel drug delivery technique that uses positive infusion pressure to deliver therapeutic agents directly into the interstitial spaces of the brain. Despite the promise of CED, clinical trials have demonstrated that target-tissue anatomy and patient-specific physiology play a major role in drug distribution using this technique. In this study, we retrospectively tested the ability of a software algorithm using MR diffusion tensor imaging to predict patient-specific drug distributions by CED. A tumor-targeted cytotoxin, cintredekin besudotox (interleukin 13-PE38QQR), was coinfused with iodine 123-labeled human serum albumin (123I-HSA), in patients with recurrent malignant gliomas. The spatial distribution of 123I-HSA was then compared to a drug distribution simulation provided by the software algorithm. The algorithm had a high sensitivity (71.4%) and specificity (100%) for identifying the high proportion (7 of 14) of catheter trajectories that failed to deliver drug into the desired anatomical region (p = 0.021). This usually occurred when catheter trajectories crossed deep sulci, resulting in leak of the infusate into the subarachnoid cerebrospinal fluid space. The mean concordance of the volume of distribution at the 50% isodose level between the actual 123I-HSA distribution and simulation was 65.75% (95% confidence interval [CI], 52.0%-79.5%), and the mean maximal inplane deviation was less than 8.5 mm (95% CI, 4.0-13.0 mm). The use of this simulation algorithm was considered clinically useful in 84.6% of catheters. Routine use of this algorithm, and its further developments, should improve prospective selection of catheter trajectories, and thereby improve the efficacy of drugs delivered by this promising technique.

Authors
Sampson, JH; Raghavan, R; Brady, ML; Provenzale, JM; Herndon, JE; Croteau, D; Friedman, AH; Reardon, DA; Coleman, RE; Wong, T; Bigner, DD; Pastan, I; Rodríguez-Ponce, MI; Tanner, P; Puri, R; Pedain, C
MLA Citation
Sampson, JH, Raghavan, R, Brady, ML, Provenzale, JM, Herndon, JE, Croteau, D, Friedman, AH, Reardon, DA, Coleman, RE, Wong, T, Bigner, DD, Pastan, I, Rodríguez-Ponce, MI, Tanner, P, Puri, R, and Pedain, C. "Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions." Neuro Oncol 9.3 (July 2007): 343-353.
PMID
17435179
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
3
Publish Date
2007
Start Page
343
End Page
353
DOI
10.1215/15228517-2007-007

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PURPOSE: Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). PATIENTS AND METHOD: Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS: Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. CONCLUSION: Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Authors
Desjardins, A; Quinn, JA; Vredenburgh, JJ; Sathornsumetee, S; Friedman, AH; Herndon, JE; McLendon, RE; Provenzale, JM; Rich, JN; Sampson, JH; Gururangan, S; Dowell, JM; Salvado, A; Friedman, HS; Reardon, DA
MLA Citation
Desjardins, A, Quinn, JA, Vredenburgh, JJ, Sathornsumetee, S, Friedman, AH, Herndon, JE, McLendon, RE, Provenzale, JM, Rich, JN, Sampson, JH, Gururangan, S, Dowell, JM, Salvado, A, Friedman, HS, and Reardon, DA. "Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas." J Neurooncol 83.1 (May 2007): 53-60.
PMID
17245623
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
83
Issue
1
Publish Date
2007
Start Page
53
End Page
60
DOI
10.1007/s11060-006-9302-2

Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function.

PURPOSE: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4(+) T cell numbers and function. We have previously shown that increased regulatory T cell (T(reg)) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model. EXPERIMENTAL DESIGN: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4(+) T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4(+)CD25(-) responder T cells were evaluated. RESULTS: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4(+)CD25(+)Foxp3(+)GITR(+) regulatory T cell fraction observed in tumor-bearing mice. CD4(+) T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4(+)CD25(-) T cell population and not T(regs), as CD4(+)CD25(-) T cells from treated mice show improved proliferative responses and resistance to T(reg)-mediated suppression, whereas T(regs) from the same mice remain anergic and exhibit no restriction of their suppressive capacity. CONCLUSIONS: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to T(reg)-mediated suppression, and not through direct effects on T(regs).

Authors
Fecci, PE; Ochiai, H; Mitchell, DA; Grossi, PM; Sweeney, AE; Archer, GE; Cummings, T; Allison, JP; Bigner, DD; Sampson, JH
MLA Citation
Fecci, PE, Ochiai, H, Mitchell, DA, Grossi, PM, Sweeney, AE, Archer, GE, Cummings, T, Allison, JP, Bigner, DD, and Sampson, JH. "Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function." Clin Cancer Res 13.7 (April 1, 2007): 2158-2167.
PMID
17404100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
7
Publish Date
2007
Start Page
2158
End Page
2167
DOI
10.1158/1078-0432.CCR-06-2070

Viruses in the treatment of malignant glioma.

Authors
Everson, RG; Gromeier, M; Sampson, JH
MLA Citation
Everson, RG, Gromeier, M, and Sampson, JH. "Viruses in the treatment of malignant glioma." Expert Rev Neurother 7.4 (April 2007): 321-324. (Review)
PMID
17425484
Source
pubmed
Published In
Expert Review of Neurotherapeutics
Volume
7
Issue
4
Publish Date
2007
Start Page
321
End Page
324
DOI
10.1586/14737175.7.4.321

High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients.

PURPOSE: To report our recent experience managing four patients with brain metastases of gestational trophoblastic neoplasia (GTN), coordinating systemic chemotherapy with early neurosurgical intervention or stereotactic radiosurgery and intensive supportive care during initial therapy to prevent early mortality. MATERIALS AND METHODS: A series of four consecutive patients with brain metastases from high-risk Stage IV GTN managed at our institution in 2003 and 2005. Patients were assigned FIGO stage and risk score prospectively. Because of concern for chronic toxicity resulting from concurrent moderate dose methotrexate and whole brain radiation, an individualized multidisciplinary approach was used to manage patients. RESULTS: All four women presented with brain and pulmonary metastases; one had multiple liver metastases. Neurological symptoms at presentation included grand mal seizures in 2 patients, left upper extremity hemiparesis and headache each in 1 patient, while 1 patient was asymptomatic. Index pregnancies were term pregnancies in all patients with interval from prior delivery ranging from 2 weeks to 4 years. Two had received prior chemotherapy for postmolar GTN prior to the index pregnancy with incomplete follow-up. Initial hCG values ranged from 26,400 to 137,751 mIU/ml; FIGO risk scores were > or =16 for all patients. Systemic combination chemotherapy was initiated with etoposide and cisplatin followed by moderate/high-dose (500-1000 mg/m(2)) methotrexate combinations. Craniotomy was used before or during the first chemotherapy cycle to extirpate solitary lesions in 3 patients, while stereotactic radiosurgery was administered after the first cycle to treat two brain lesions in the remaining patient. None received whole brain radiation or intrathecal methotrexate. In one patient, selective angiographic embolization was used to control hemorrhage from multiple liver metastases. Two patients required ventilator support early in treatment to allow stabilization from intrathoracic hemorrhage and neutropenic sepsis with respiratory distress syndrome, respectively. Hysterectomy was performed in one patient after completion of salvage chemotherapy. All have completed maintenance chemotherapy and are in prolonged remission (12-24 months). Neurologic sequelae include persistent left upper extremity dyskinesia and weakness in one patient, and episodic grand mal seizures and pseudoseizures in a second patient with a pre-existing seizure disorder. CONCLUSION: This case series documents the utility for a multidisciplinary approach to the treatment of brain metastases from GTN. Using early craniotomy or stereotactic radiosurgery combined with etoposide-cisplatin and moderate/high-dose methotrexate combination chemotherapy, we were able to stabilize patients early in their treatment and avoid whole brain radiation therapy or intrathecal chemotherapy.

Authors
Soper, JT; Spillman, M; Sampson, JH; Kirkpatrick, JP; Wolf, JK; Clarke-Pearson, DL
MLA Citation
Soper, JT, Spillman, M, Sampson, JH, Kirkpatrick, JP, Wolf, JK, and Clarke-Pearson, DL. "High-risk gestational trophoblastic neoplasia with brain metastases: individualized multidisciplinary therapy in the management of four patients." Gynecol Oncol 104.3 (March 2007): 691-694.
PMID
17137617
Source
pubmed
Published In
Gynecologic Oncology
Volume
104
Issue
3
Publish Date
2007
Start Page
691
End Page
694
DOI
10.1016/j.ygyno.2006.10.027

Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin.

OBJECTIVE: Convection-enhanced delivery is a promising approach to intracerebral drug delivery in which a fluid pressure gradient is used to infuse therapeutic macromolecules through an indwelling catheter into the interstitial spaces of the brain. Our purpose was to test the hypothesis that hyperintense signal changes on T2-weighted images produced by such infusions can be used to track drug distribution. SUBJECTS AND METHODS: Seven adults with recurrent malignant glioma underwent concurrent intracerebral infusions of the tumor-targeted cytotoxin cintredekin besudotox and 123I-labeled human serum albumin. The agents were administered through a total of 18 catheters among the seven patients. Adequacy of distribution of drug was determined by evidence of distribution of 123I-labeled human serum albumin on SPECT images coregistered with MR images. Qualitative analysis was performed by three blinded observers. Quantitative analysis also was performed. RESULTS: Infusions into 12 catheters produced intraparenchymal distribution as seen on SPECT images, but infusions into six catheters did not. At qualitative assessment of signal changes on MR images, reviewers correctly predicted which catheters would produce extraparenchymal distribution and which catheters would produce parenchymal distribution. Of the 12 infusions that produced intraparenchymal distribution, four catheters had been placed in regions of relatively normal signal intensity and produced regions of newly increased signal intensity, the volume of which highly correlated with the volume and geometry of distribution on SPECT (r2 = 0.9502). Eight infusions that produced intraparenchymal distribution were performed in regions of preexisting hyperintense signal. In these brains, additional signal changes were always produced, but quantitative correlations between areas of newly increased signal intensity and the volume and geometry of distribution on SPECT could not be established. CONCLUSION: Convection-enhanced infusions frequently do not provide intraparenchymal drug distribution, and these failures can be identified with MRI soon after infusion. When infusions are performed into regions of normal signal intensity, development of hyperintense signal change strongly correlates with the volume and geometry of distribution of infusate.

Authors
Sampson, JH; Raghavan, R; Provenzale, JM; Croteau, D; Reardon, DA; Coleman, RE; Rodríguez Ponce, I; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, JH, Raghavan, R, Provenzale, JM, Croteau, D, Reardon, DA, Coleman, RE, Rodríguez Ponce, I, Pastan, I, Puri, RK, and Pedain, C. "Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin." AJR Am J Roentgenol 188.3 (March 2007): 703-709.
PMID
17312057
Source
pubmed
Published In
AJR. American journal of roentgenology
Volume
188
Issue
3
Publish Date
2007
Start Page
703
End Page
709
DOI
10.2214/AJR.06.0428

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning

OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery. Copyright © by the Congress of Neurological Surgeons.

Authors
Sampson, JH; Brady, ML; Petry, NA; Croteau, D; Friedman, AH; Friedman, HS; Wong, T; Bigner, DD; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, JH, Brady, ML, Petry, NA, Croteau, D, Friedman, AH, Friedman, HS, Wong, T, Bigner, DD, Pastan, I, Puri, RK, and Pedain, C. "Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning." Neurosurgery 60.2 SUPPL.1 (February 1, 2007).
Source
scopus
Published In
Neurosurgery
Volume
60
Issue
2 SUPPL.1
Publish Date
2007
DOI
10.1227/01.NEU.0000249256.09289.5F

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning.

OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.

Authors
Sampson, JH; Brady, ML; Petry, NA; Croteau, D; Friedman, AH; Friedman, HS; Wong, T; Bigner, DD; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, JH, Brady, ML, Petry, NA, Croteau, D, Friedman, AH, Friedman, HS, Wong, T, Bigner, DD, Pastan, I, Puri, RK, and Pedain, C. "Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning." Neurosurgery 60.2 Suppl 1 (February 2007): ONS89-ONS98.
PMID
17297371
Source
pubmed
Published In
Neurosurgery
Volume
60
Issue
2 Suppl 1
Publish Date
2007
Start Page
ONS89
End Page
ONS98
DOI
10.1227/01.NEU.0000249256.09289.5F

Genetic analysis of intracranial tumors in a murine model of glioma demonstrate a shift in gene expression in response to host immunity.

For the study of malignant glioma, we have previously characterized a highly tumorigenic murine astrocytoma, SMA-560, which arose spontaneously in an inbred, immunocompetent VM/Dk mouse. Using this cell line as a model of murine glioma, we performed DNA microarray analysis of autologous normal murine astroctyes (NMA) and SMA-560 tumor cells grown in monolayer culture or intracranially in syngeneic immunocompetent or immunocompromised hosts in order to determine whether tumors grown in vitro recreate the complex genetic regulation that occurs in vivo. Our findings support our hypothesis that glioma phenotype in vitro may be quite different in vivo and significantly altered by in situ growth factors and other invading cell populations.

Authors
Learn, CA; Grossi, PM; Schmittling, RJ; Xie, W; Mitchell, DA; Karikari, I; Wei, Z; Dressman, H; Sampson, JH
MLA Citation
Learn, CA, Grossi, PM, Schmittling, RJ, Xie, W, Mitchell, DA, Karikari, I, Wei, Z, Dressman, H, and Sampson, JH. "Genetic analysis of intracranial tumors in a murine model of glioma demonstrate a shift in gene expression in response to host immunity." Journal of neuroimmunology 182.1-2 (January 2007): 63-72.
PMID
17137636
Source
epmc
Published In
Journal of Neuroimmunology
Volume
182
Issue
1-2
Publish Date
2007
Start Page
63
End Page
72
DOI
10.1016/j.jneuroim.2006.09.016

Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: A report by the cintredekin besudotox intraparenchymal study group

Purpose: Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG). Patients and Methods: Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion. Results: A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 μg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years. Conclusion: CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome. © 2007 by American Society of Clinical Oncology.

Authors
Kunwar, S; Prados, MD; Chang, SM; Berger, MS; Lang, FF; Piepmeier, JM; Sampson, JH; Ram, Z; Gutin, PH; Gibbons, RD; Aldape, KD; Croteau, DJ; Sherman, JW; Puri, RK
MLA Citation
Kunwar, S, Prados, MD, Chang, SM, Berger, MS, Lang, FF, Piepmeier, JM, Sampson, JH, Ram, Z, Gutin, PH, Gibbons, RD, Aldape, KD, Croteau, DJ, Sherman, JW, and Puri, RK. "Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: A report by the cintredekin besudotox intraparenchymal study group." Journal of Clinical Oncology 25.7 (2007): 837-844.
PMID
17327604
Source
scival
Published In
Journal of Clinical Oncology
Volume
25
Issue
7
Publish Date
2007
Start Page
837
End Page
844
DOI
10.1200/JCO.2006.08.1117

Convection-enhanced delivery of cintredekin besudotox (interleukin-13- PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: Phase 1 study of final safety results

OBJECTIVE: Cintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13Rα2 receptors overexpressed by malignant gliomas. This study assessed the safety of CB administered by convection-enhanced delivery followed by standard external beam radiation therapy (EBRT) with or without temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) in patients with newly diagnosed malignant gliomas. METHODS: After gross total resection of the tumor, two to four intraparenchymal catheters were stereotactically placed and CB (0.25 or 0.5 μg/mL) was infused for 96 hours. This was followed, 10 to 14 days later, by EBRT (5940-6100 cGy, 5 d/wk for 6-7 wk) with or without temozolomide (75 mg/m/d, 7 d/wk during EBRT). Safety was assessed during an 11-week observation period after catheter placement RESULTS: Twenty-two patients (12 men, 10 women; median age, 55 yr; 21 with glioblastoma multiforme and one with an anaplastic mixed oligoastrocytoma) were enrolled. None of the patients experienced dose-limiting toxicities in the first two cohorts (0.25 μg/mL CB + EBRT [n = 3] and 0.25 μg/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 μg/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 μg/mL CB + EBRT + temozolomide [n = 10]) completed treatment, and one patient experienced a dose-limiting toxicity (Grade 3 aphasia and confusion). Four patients were not considered evaluable for a dose decision and were replaced. CB related adverse events occurring in more than one patient were fatigue, gait disturbance, nystagmus, and confusion. No Grade 3 to 4 hematological toxicities were observed. CONCLUSION: CB (0.5 μg/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted. Copyright © by the Congress of Neurological Surgeons.

Authors
Vogelbaum, MA; Sampson, JH; Kunwar, S; Chang, SM; Shaffrey, M; Asher, AL; Lang, FF; Croteau, D; Parker, K; Grahn, AY; Sherman, JW; Husain, SR; Puri, RK
MLA Citation
Vogelbaum, MA, Sampson, JH, Kunwar, S, Chang, SM, Shaffrey, M, Asher, AL, Lang, FF, Croteau, D, Parker, K, Grahn, AY, Sherman, JW, Husain, SR, and Puri, RK. "Convection-enhanced delivery of cintredekin besudotox (interleukin-13- PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: Phase 1 study of final safety results." Neurosurgery 61.5 (2007): 1031-1037.
PMID
18091279
Source
scival
Published In
Neurosurgery
Volume
61
Issue
5
Publish Date
2007
Start Page
1031
End Page
1037
DOI
10.1227/01.neu.0000303199.77370.9e

Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers.

PURPOSE: Analyses of T-cell mRNA expression profiles in glioblastoma multiforme has not been previously reported but may help to define and characterize the immunosuppressed phenotype in patients with this type of cancer. EXPERIMENTAL DESIGN: We did microarray studies that have shown significant and fundamental differences in the expression profiles of CD4(+) and CD8(+) T cells and immunosuppressive CD4(+)CD25(+)CD45RO(+)FoxP3(+) regulatory T cells (T(reg)) from normal healthy volunteers compared with patients with newly diagnosed glioblastoma multiforme. For these investigations, we isolated total RNA from enriched CD4(+) and CD8(+) T cell or T(reg) cell populations from age-matched individuals and did microarray analyses. RESULTS: ANOVA and principal components analysis show that the various T cell compartments exhibit consistently similar mRNA expression profiles among individuals within either healthy or brain tumor groups but reflect significant differences between these groups. Compared with healthy volunteers, CD4(+) and CD8(+) T cells from patients with glioblastoma multiforme display coordinate down-regulation of genes involved in T cell receptor ligation, activation, and intracellular signaling. In contrast, T(regs) from patients with glioblastoma multiforme exhibit increased levels of transcripts involved in inhibiting host immunity. CONCLUSION: Our findings support the notion that key differences between expression profiles in T-cell populations from patients with glioblastoma multiforme results from differential expression of the immunologic transcriptome, such that a limited number of genes are principally important in producing the dysregulated T-cell phenotype.

Authors
Learn, CA; Fecci, PE; Schmittling, RJ; Xie, W; Karikari, I; Mitchell, DA; Archer, GE; Wei, Z; Dressman, H; Sampson, JH
MLA Citation
Learn, CA, Fecci, PE, Schmittling, RJ, Xie, W, Karikari, I, Mitchell, DA, Archer, GE, Wei, Z, Dressman, H, and Sampson, JH. "Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T cells in patients with malignant glioma reveals differential expression of the immunologic transcriptome compared with T cells from healthy volunteers." Clinical cancer research : an official journal of the American Association for Cancer Research 12.24 (December 2006): 7306-7315.
PMID
17189402
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
24
Publish Date
2006
Start Page
7306
End Page
7315
DOI
10.1158/1078-0432.ccr-06-1727

Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin.

The topoisomerase I inhibitor, 9-nitro-camptothecin (9NC), is highly tumoricidal against glioblastoma multiforme (GBM) in vitro. However, systemic administration of 9NC has not shown the expected efficacy in clinical trials. This failure may be due to the rapid hydrolysis of 9NC in plasma from the active form to the inactive and myelosuppressive form in the presence of human albumin at physiologic pH. Concurrent treatment with anticonvulsants and dexamethasone, drugs indispensable for the supportive therapy of patients with GBM, has also been shown to decrease plasma concentrations of these drugs. Intrathecal drug delivery circumvents the blood-brain barrier and minimizes systemic toxicity. Intrathecal delivery of 9NC may also have the more specific advantage of significantly reducing the hydrolysis of 9NC that occurs after systemic delivery due to the more favorable pH and reduced albumin content in cerebrospinal fluid. The present study evaluated the toxicity and efficacy of intrathecal delivery of 9NC in an athymic rat model of neoplastic meningitis. Toxicity tests showed that 0.3 micromol (5000 microM), 0.03 micromol (500 microM), 0.003 micromol (50 microM), or 0.0003 micromol (5 microM) of 9NC administered intrathecally to the athymic rats caused no evidence of clinical or histological toxicity. Intrathecal administration of 0.3 micromol (5000 microM) of 9NC twice a week for three doses to athymic rats with neoplastic meningitis induced by the GBM cell line, U87MGDeltaEGFR, resulted in a 26% increase of median survival compared to the control group (p < 0.005). These results suggest that intrathecal treatment with 9NC may be useful for patients with GBM neoplastic meningitis.

Authors
Ochiai, H; Pernell, CT; Archer, GE; Chewning, TA; McLendon, RE; Friedman, HS; Sampson, JH
MLA Citation
Ochiai, H, Pernell, CT, Archer, GE, Chewning, TA, McLendon, RE, Friedman, HS, and Sampson, JH. "Treatment of neoplastic meningitis with intrathecal 9-nitro-camptothecin." Neurol Med Chir (Tokyo) 46.10 (October 2006): 485-489.
PMID
17062987
Source
pubmed
Published In
Neurologia medico-chirurgica
Volume
46
Issue
10
Publish Date
2006
Start Page
485
End Page
489

Preoperative functional MR imaging localization of language and motor areas: effect on therapeutic decision making in patients with potentially resectable brain tumors.

PURPOSE: To prospectively evaluate the effect of preoperative functional magnetic resonance (MR) imaging localization of language and motor areas on therapeutic decision making in patients with potentially resectable brain tumors. MATERIALS AND METHODS: The Institutional Review Board approved this HIPAA-compliant study, and each patient gave written informed consent. Thirty-nine consecutive patients (19 male, 20 female; mean age, 42.2 years) referred for functional MR imaging for possible tumor resection were prospectively evaluated. A preoperative diagnosis of brain tumor was made in all patients. Sentence completion and bilateral hand squeeze tasks were used to map language and sensory motor areas. Neurosurgeons completed questionnaires regarding the proposed treatment plan before and after functional MR imaging and after surgery. They also gave confidence ratings for functional MR imaging results and estimated the effect on surgical time, extent of resection, and surgical approach. The effect of functional MR imaging on changes in treatment plan was assessed with the Wilcoxon signed rank test. Differences in confidence ratings between altered and unaltered treatment plans were assessed with the Mann-Whitney U test. The estimated influence of functional MR imaging on surgical time, extent of resection, and surgical approach was denoted with summary statistics. RESULTS: Treatment plans before and after functional MR imaging differed in 19 patients (P < .05), with a more aggressive approach recommended after imaging in 18 patients. There were no significant differences in confidence ratings for functional MR imaging between altered and unaltered plans. Functional MR imaging resulted in reduced surgical time (estimated reduction, 15-60 minutes) in 22 patients who underwent surgery, a more aggressive resection in six, and a smaller craniotomy in two. CONCLUSION: Functional MR imaging enables the selection of a more aggressive therapeutic approach than might otherwise be considered because of functional risk. In certain patients, surgical time may be shortened, the extent of resection increased, and craniotomy size decreased.

Authors
Petrella, JR; Shah, LM; Harris, KM; Friedman, AH; George, TM; Sampson, JH; Pekala, JS; Voyvodic, JT
MLA Citation
Petrella, JR, Shah, LM, Harris, KM, Friedman, AH, George, TM, Sampson, JH, Pekala, JS, and Voyvodic, JT. "Preoperative functional MR imaging localization of language and motor areas: effect on therapeutic decision making in patients with potentially resectable brain tumors." Radiology 240.3 (September 2006): 793-802.
PMID
16857981
Source
pubmed
Published In
Radiology
Volume
240
Issue
3
Publish Date
2006
Start Page
793
End Page
802
DOI
10.1148/radiol.2403051153

Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells.

PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens. RESULTS: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.

Authors
Fecci, PE; Sweeney, AE; Grossi, PM; Nair, SK; Learn, CA; Mitchell, DA; Cui, X; Cummings, TJ; Bigner, DD; Gilboa, E; Sampson, JH
MLA Citation
Fecci, PE, Sweeney, AE, Grossi, PM, Nair, SK, Learn, CA, Mitchell, DA, Cui, X, Cummings, TJ, Bigner, DD, Gilboa, E, and Sampson, JH. "Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells." Clin Cancer Res 12.14 Pt 1 (July 15, 2006): 4294-4305.
PMID
16857805
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
14 Pt 1
Publish Date
2006
Start Page
4294
End Page
4305
DOI
10.1158/1078-0432.CCR-06-0053

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, DA, Quinn, JA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Dowell, JM, Rich, JN, Vredenburgh, JJ, Desjardins, A, Sampson, JH, Gururangan, S, Wong, TZ, Badruddoja, MA, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results." J Nucl Med 47.6 (June 2006): 912-918.
PMID
16741299
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies.

OBJECTIVES: Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection. METHODS: Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the 123I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a 131I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography. CONCLUSIONS: Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.

Authors
Sampson, JH; Akabani, G; Friedman, AH; Bigner, D; Kunwar, S; Berger, MS; Bankiewicz, KS
MLA Citation
Sampson, JH, Akabani, G, Friedman, AH, Bigner, D, Kunwar, S, Berger, MS, and Bankiewicz, KS. "Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies. (Published online)" Neurosurg Focus 20.4 (April 15, 2006): E14-.
PMID
16709019
Source
pubmed
Published In
Neurosurgical focus
Volume
20
Issue
4
Publish Date
2006
Start Page
E14
DOI
10.3171/foc.2006.20.4.9

Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.

Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.

Authors
Fecci, PE; Mitchell, DA; Whitesides, JF; Xie, W; Friedman, AH; Archer, GE; Herndon, JE; Bigner, DD; Dranoff, G; Sampson, JH
MLA Citation
Fecci, PE, Mitchell, DA, Whitesides, JF, Xie, W, Friedman, AH, Archer, GE, Herndon, JE, Bigner, DD, Dranoff, G, and Sampson, JH. "Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma." Cancer Res 66.6 (March 15, 2006): 3294-3302.
PMID
16540683
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
6
Publish Date
2006
Start Page
3294
End Page
3302
DOI
10.1158/0008-5472.CAN-05-3773

Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus.

PURPOSE: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis. EXPERIMENTAL DESIGN: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft. RESULTS: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P < 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10(9) pfu PVS-RIPO (P < 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO-treated group and 3 of 10 rats in higher-dose PVS-RIPO-treated group survived >60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy. CONCLUSION: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.

Authors
Ochiai, H; Campbell, SA; Archer, GE; Chewning, TA; Dragunsky, E; Ivanov, A; Gromeier, M; Sampson, JH
MLA Citation
Ochiai, H, Campbell, SA, Archer, GE, Chewning, TA, Dragunsky, E, Ivanov, A, Gromeier, M, and Sampson, JH. "Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus." Clin Cancer Res 12.4 (February 15, 2006): 1349-1354.
PMID
16489093
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
4
Publish Date
2006
Start Page
1349
End Page
1354
DOI
10.1158/1078-0432.CCR-05-1595

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Desjardins, A; Sathornsumetee, S; Herndon, JE; Dowell, JM; McLendon, RE; Provenzale, JM; Sampson, JH; Smith, RP; Swaisland, AJ; Ochs, JS; Lyons, P; Tourt-Uhlig, S; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Reardon, DA, Quinn, JA, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Desjardins, A, Sathornsumetee, S, Herndon, JE, Dowell, JM, McLendon, RE, Provenzale, JM, Sampson, JH, Smith, RP, Swaisland, AJ, Ochs, JS, Lyons, P, Tourt-Uhlig, S, Bigner, DD, Friedman, HS, and Rich, JN. "Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 860-868.
PMID
16467100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
860
End Page
868
DOI
10.1158/1078-0432.CCR-05-2215

Convection-enhanced delivery of therapeutics for brain disease, and its optimization.

Convection-enhanced delivery (CED) is the continuous injection under positive pressure of a fluid containing a therapeutic agent. This technique was proposed and introduced by researchers from the US National Institutes of Health (NIH) by the early 1990s to deliver drugs that would otherwise not cross the blood-brain barrier into the parenchyma and that would be too large to diffuse effectively over the required distances were they simply deposited into the tissue. Despite the many years that have elapsed, this technique remains experimental because of both the absence of approved drugs for intraparenchymal delivery and the difficulty of guaranteed delivery to delineated regions of the brain. During the first decade after the NIH researchers founded this analytical model of drug distribution, the results of several computer simulations that had been conducted according to more realistic assumptions were also published, revealing encouraging results. In the late 1990s, one of the authors of the present paper proposed the development of a computer model that would predict the distribution specific to a particular patient (brain) based on obtainable data from radiological images. Several key developments in imaging technology and, in particular, the relationships between image-obtained quantities and other parameters that enter models of the CED process have been required to implement this model. Note that delivery devices need further development. In the present paper we review key features of CED as well as modeling of the procedure and indulge in informed speculation on optimizing the direct delivery of therapeutic agents into brain tissue.

Authors
Raghavan, R; Brady, ML; Rodríguez-Ponce, MI; Hartlep, A; Pedain, C; Sampson, JH
MLA Citation
Raghavan, R, Brady, ML, Rodríguez-Ponce, MI, Hartlep, A, Pedain, C, and Sampson, JH. "Convection-enhanced delivery of therapeutics for brain disease, and its optimization." Neurosurgical focus 20.4 (2006): E12-.
PMID
16709017
Source
scival
Published In
Neurosurgical focus
Volume
20
Issue
4
Publish Date
2006
Start Page
E12
DOI
10.3171/foc.2006.20.4.7

Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies.

OBJECT: Convection-enhanced delivery (CED) is an increasingly used novel local/regional delivery method targeted directly to tissue. It relies on a continuous pressure gradient for distribution of therapeutic agents into the interstitial space, with administration of the infusate over a few days. Cintredekin besudotox (also known as IL13- PE38QQR) is a recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium, which targets malignant glioma cells. METHODS: Cintredekin besudotox was administered via intraparenchymal CED after resection of supratentorial recurrent malignant glioma. The safety and toxicity profile was reviewed for 53 patients in whom infusion catheters had been placed; 51 of them received CED of the study drug. Adverse events were categorized based on time of onset in relation to CED, and the causal relationship with catheter placement or delivery of cintredekin besudotox. Catheters were placed in 53 patients, although only 51 of them received cintredekin besudotox. Most adverse events related to catheter placement or the study drug originated from the central nervous system. Three symptomatic windows were defined: the first one was between surgical procedure and CED; the second was during CED and up to 1 week after its completion; and the third window was 2 to 10 weeks after treatment. Those windows generally reflected adverse events related to surgical procedures, mass effect from infusate, and drug effect on tumor-infiltrated and normal brain parenchyma, respectively. CONCLUSIONS: The symptomatic windows identified in this study apply to any CED clinical trials, particularly those in which chimeric cytotoxins are used, and will help to determine the most likely underlying pathophysiological process causing symptoms. This information, in turn, will help to prevent adverse events or minimize their severity. Those events also have implications for dose escalation and outcome measures.

Authors
Kunwar, S; Chang, SM; Prados, MD; Berger, MS; Sampson, JH; Croteau, D; Sherman, JW; Grahn, AY; Shu, VS; Dul, JL; Husain, SR; Joshi, BH; Pedain, C; Puri, RK
MLA Citation
Kunwar, S, Chang, SM, Prados, MD, Berger, MS, Sampson, JH, Croteau, D, Sherman, JW, Grahn, AY, Shu, VS, Dul, JL, Husain, SR, Joshi, BH, Pedain, C, and Puri, RK. "Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies." Neurosurgical focus [electronic resource]. 20.4 (2006): E15-.
PMID
16709020
Source
scival
Published In
Neurosurgical focus
Volume
20
Issue
4
Publish Date
2006
Start Page
E15

Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS). RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea. CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Authors
Reardon, DA; Egorin, MJ; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Provenzale, JM; Herndon, JE; Dowell, JM; Badruddoja, MA; McLendon, RE; Lagattuta, TF; Kicielinski, KP; Dresemann, G; Sampson, JH; Friedman, AH; Salvado, AJ; Friedman, HS
MLA Citation
Reardon, DA, Egorin, MJ, Quinn, JA, Rich, JN, Gururangan, S, Vredenburgh, JJ, Desjardins, A, Sathornsumetee, S, Provenzale, JM, Herndon, JE, Dowell, JM, Badruddoja, MA, McLendon, RE, Lagattuta, TF, Kicielinski, KP, Dresemann, G, Sampson, JH, Friedman, AH, Salvado, AJ, and Friedman, HS. "Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme." J Clin Oncol 23.36 (December 20, 2005): 9359-9368.
PMID
16361636
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
36
Publish Date
2005
Start Page
9359
End Page
9368
DOI
10.1200/JCO.2005.03.2185

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Authors
Quinn, JA; Desjardins, A; Weingart, J; Brem, H; Dolan, ME; Delaney, SM; Vredenburgh, J; Rich, J; Friedman, AH; Reardon, DA; Sampson, JH; Pegg, AE; Moschel, RC; Birch, R; McLendon, RE; Provenzale, JM; Gururangan, S; Dancey, JE; Maxwell, J; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Desjardins, A, Weingart, J, Brem, H, Dolan, ME, Delaney, SM, Vredenburgh, J, Rich, J, Friedman, AH, Reardon, DA, Sampson, JH, Pegg, AE, Moschel, RC, Birch, R, McLendon, RE, Provenzale, JM, Gururangan, S, Dancey, JE, Maxwell, J, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 23.28 (October 1, 2005): 7178-7187.
PMID
16192602
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
28
Publish Date
2005
Start Page
7178
End Page
7187
DOI
10.1200/JCO.2005.06.502

Surgical management of petroclival meningiomas: defining resection goals based on risk of neurological morbidity and tumor recurrence rates in 137 patients.

OBJECTIVE: Meningiomas arising from the petroclival region remain a challenging surgical problem. Because of the substantial risk of neurological morbidity, uniformly pursuing a gross total resection (GTR) to minimize tumor recurrence rates may not be justified. We sought to define optimal resection goals based on risk factors for postoperative neurological morbidity and tumor recurrence rates. METHODS: This series represents our experience with 137 meningiomas arising from the petroclival region resected between June 1993 and October 2002. There were 38 male and 99 female patients with a mean age of 53 years. RESULTS: GTR was achieved in 40% of patients, and near total resection (NTR) was achieved in 40% of patients. One operative death occurred. Twenty-six percent of patients experienced new postoperative cranial nerve deficits, paresis, or ataxia when assessed at a mean follow-up of 8.3 months. The risk of cranial nerve deficits increased with prior resection (P < 0.001), preoperative cranial nerve deficit (P = 0.005), tumor adherence to neurovascular structures (P = 0.046), and fibrous tumor consistency (P = 0.005). The risk of paresis or ataxia increased with prior resection (P = 0.001) and tumor adherence (P = 0.045). Selective NTR rather than GTR in patients with adherent or fibrous tumors significantly reduced the rate of neurological deficits. Radiographic recurrence or progression occurred in 17.6% of patients at a mean follow-up of 29.8 months. Tumor recurrence rates after GTR and NTR did not differ significantly (P = 0.111). CONCLUSION: Intraoperatively defined tumor characteristics played a critical role in identifying the subset of patients with an increased risk of postoperative deficits. By selectively pursuing an NTR rather than a GTR, neurological morbidity was reduced significantly without significantly increasing the rate of tumor recurrence.

Authors
Little, KM; Friedman, AH; Sampson, JH; Wanibuchi, M; Fukushima, T
MLA Citation
Little, KM, Friedman, AH, Sampson, JH, Wanibuchi, M, and Fukushima, T. "Surgical management of petroclival meningiomas: defining resection goals based on risk of neurological morbidity and tumor recurrence rates in 137 patients." Neurosurgery 56.3 (March 2005): 546-559. (Review)
PMID
15730581
Source
pubmed
Published In
Neurosurgery
Volume
56
Issue
3
Publish Date
2005
Start Page
546
End Page
559

Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study.

Glioblastoma multiforme remains refractory to conventional therapy, and novel therapeutic modalities are desperately needed. TP-38 is a recombinant chimeric protein containing a genetically engineered form of the cytotoxic Pseudomonas exotoxin fused to transforming growth factor (TGF)-alpha. TGF-alpha binds with high affinity to the epidermal growth factor receptor, which is uniformly overexpressed in malignant gliomas, often because of gene amplification. Prior to therapy with TP-38, the patient described here was completely refractory to multiple other therapies, with radiographic and pathologic evidence of tumor progression. After therapy, she improved clinically, was weaned off steroids and anti-convulsants, and experienced a progressive decrease in enhancing tumor volume. Despite multiple prior recurrences, she has not progressed for >43 months after TP-38 therapy. Small remaining areas of enhancement demonstrate no evidence of tumor histologically and are hypometabolic on positron emission tomography. This report describes a dramatic and sustained clinical and radiographic response in a patient with a bifrontal glioblastoma multiforme treated with intratumoral infusion of a novel targeted toxin, TP-38.

Authors
Sampson, JH; Reardon, DA; Friedman, AH; Friedman, HS; Coleman, RE; McLendon, RE; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Reardon, DA, Friedman, AH, Friedman, HS, Coleman, RE, McLendon, RE, Pastan, I, and Bigner, DD. "Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study." Neuro Oncol 7.1 (January 2005): 90-96.
PMID
15701286
Source
pubmed
Published In
Neuro-Oncology
Volume
7
Issue
1
Publish Date
2005
Start Page
90
End Page
96
DOI
10.1215/S1152851703000589

Brain metastases from malignant melanoma

Authors
Sampson, JH; Shafman, TD; Carter, JH; Friedman, AH; Seigler, HF
MLA Citation
Sampson, JH, Shafman, TD, Carter, JH, Friedman, AH, and Seigler, HF. "Brain metastases from malignant melanoma." Textbook of Neuro-Oncology (2005): 430-438.
Source
scival
Published In
Textbook of Neuro-Oncology
Publish Date
2005
Start Page
430
End Page
438
DOI
10.1016/B978-0-7216-8148-1.50059-0

Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus.

PURPOSE: Spread to the central nervous system (CNS) and the leptomeninges is a frequent complication of systemic cancers that is associated with serious morbidity and high mortality. We have evaluated a novel therapeutic approach against CNS complications of breast cancer based on the human neuropathogen poliovirus (PV). EXPERIMENTAL DESIGN: Susceptibility to PV infection and ensuing rapid cell lysis is mediated by the cellular receptor of PV, CD155. We evaluated CD155 expression in several human breast tumor tissue specimens and cultured breast cancer cell lines. In addition, we tested an oncolytic PV recombinant for efficacy in xenotransplantation models of neoplastic meningitis and cerebral metastasis secondary to breast cancer. RESULTS: We observed that breast cancer tissues and cell lines derived thereof express CD155 at levels mediating exquisite sensitivity toward PV-induced oncolysis in the latter. An association with the immunoglobulin superfamily molecule CD155 renders breast cancer a likely target for oncolytic PV recombinants. This assumption was confirmed in xenotransplantation models for neoplastic meningitis or solitary cerebral metastasis, where local virus treatment dramatically improved survival. CONCLUSIONS: Our findings suggest oncolytic PV recombinants as a viable treatment option for CNS complications of breast cancer.

Authors
Ochiai, H; Moore, SA; Archer, GE; Okamura, T; Chewning, TA; Marks, JR; Sampson, JH; Gromeier, M
MLA Citation
Ochiai, H, Moore, SA, Archer, GE, Okamura, T, Chewning, TA, Marks, JR, Sampson, JH, and Gromeier, M. "Treatment of intracerebral neoplasia and neoplastic meningitis with regional delivery of oncolytic recombinant poliovirus." Clin Cancer Res 10.14 (July 15, 2004): 4831-4838.
PMID
15269159
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
14
Publish Date
2004
Start Page
4831
End Page
4838
DOI
10.1158/1078-0432.CCR-03-0694

Poliovirus receptor CD155-targeted oncolysis of glioma.

Cell adhesion molecules of the immunoglobulin superfamily are aberrantly expressed in malignant glioma. Amongst these, the human poliovirus receptor CD155 provides a molecular target for therapeutic intervention with oncolytic poliovirus recombinants. Poliovirus has been genetically modified through insertion of regulatory sequences derived from human rhinovirus type 2 to selectively replicate within and destroy cancerous cells. Efficacious oncolysis mediated by poliovirus derivatives depends on the presence of CD155 in targeted tumors. To prepare oncolytic polioviruses for clinical application, we have developed a series of assays in high-grade malignant glioma (HGL) to characterize CD155 expression levels and susceptibility to oncolytic poliovirus recombinants. Analysis of 6 HGL cases indicates that CD155 is expressed in these tumors and in primary cell lines derived from these tumors. Upregulation of the molecular target CD155 rendered explant cultures of all studied tumors highly susceptible to a prototype oncolytic poliovirus recombinant. Our observations support the clinical application of such agents against HGL.

Authors
Merrill, MK; Bernhardt, G; Sampson, JH; Wikstrand, CJ; Bigner, DD; Gromeier, M
MLA Citation
Merrill, MK, Bernhardt, G, Sampson, JH, Wikstrand, CJ, Bigner, DD, and Gromeier, M. "Poliovirus receptor CD155-targeted oncolysis of glioma." Neuro Oncol 6.3 (July 2004): 208-217.
PMID
15279713
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
3
Publish Date
2004
Start Page
208
End Page
217
DOI
10.1215/S1152851703000577

Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme.

PURPOSE: We have reported previously that tumors expressing wild-type epidermal growth factor receptor (EGFR) in a murine model are sensitive to the EGFR tyrosine kinase inhibitor gefitinib, whereas tumors expressing mutant EGFR variant III (EGFRvIII) are resistant. Determination of how this differential inhibition occurs may be important to patient selection and treatment criteria, as well as the design of future therapeutics for glioblastoma multiforme. EXPERIMENTAL DESIGN: We have determined and quantified how treatment with gefitinib at commonly used, noncytotoxic doses affects neoplastic functions ascribed to EGFRvIII, including downstream signaling by Akt, DNA synthesis, and cellular invasion. In doing so, we have tested and compared a series of wild-type and mutant EGFRvIII-expressing fibroblast and glioblastoma cell lines in vitro after treatment with gefitinib. RESULTS: The results of these experiments demonstrate that short-term treatment with gefitinib (approximately 24 h) does not reduce phosphorylation of EGFRvIII, whereas EGFR phosphorylation is inhibited in a dose-dependent manner. However, after daily treatment with gefitinib, phosphorylation declines for EGFRvIII by day 3 and later. Nevertheless, after 7 days of daily treatment, cells that express and are dependent on EGFRvIII for tumorigenic growth are not effectively growth inhibited. This may be due in part to phosphorylation of Akt, which is inhibited in EGFR-expressing cells after treatment with gefitinib, but is unaffected in cells expressing EGFRvIII. Cell cycle analysis shows that nascent DNA synthesis in EGFR-expressing cells is inhibited in a dose-dependent manner by gefitinib, yet is unaffected in EGFRvIII-expressing cells with increasing dosage. Furthermore, cells expressing EGFRvIII demonstrate greater invasive capability with increasing gefitinib concentration when compared with cells expressing EGFR after treatment. CONCLUSIONS: We conclude that the neoplastic phenotype of EGFRvIII is relatively resistant to gefitinib and requires higher doses, repeated dosing, and longer exposure to decrease receptor phosphorylation. However, this decrease does not effectively inhibit the biologically relevant processes of DNA synthesis, cellular growth, and invasion in cells expressing EGFRvIII.

Authors
Learn, CA; Hartzell, TL; Wikstrand, CJ; Archer, GE; Rich, JN; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Learn, CA, Hartzell, TL, Wikstrand, CJ, Archer, GE, Rich, JN, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme." Clin Cancer Res 10.9 (May 1, 2004): 3216-3224.
PMID
15131063
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
9
Publish Date
2004
Start Page
3216
End Page
3224

Microvascular decompression for glossopharyngeal neuralgia: long-term effectiveness and complication avoidance.

OBJECTIVE: To establish the long-term safety, efficacy, and durability of microvascular decompression (MVD) for the treatment of glossopharyngeal neuralgia, this study presents the immediate (<6 mo) postoperative and long-term results of a large series of 47 patients with treated with MVD. METHODS: Operative reports and hospital charts were analyzed to collect demographic information, clinical presentation, and surgical findings. Surgical results and complications were ascertained by direct patient contact or by contact with the patient's family or physician if the patient was dead. Long-term (>10 yr) personal follow-up was available for 29 of 47 patients. RESULTS: Forty-six (98%) of 47 patients experienced complete relief of pain immediately after MVD. Long-term follow-up was available for 29 of these 47 patients (range, 125-211 mo; median, 152 mo, or 12.7 yr), and 28 of these 29 patients continued to be pain-free. Permanent neurological deficits (>6 mo) attributed to the surgery were observed in 5 (11%) of 47 patients. Of these patients, 4 of 5 had mild hoarseness or dysphagia or both, and one had a Grade II/VI facial nerve paresis. CONCLUSION: This study demonstrates that MVD is a safe, effective, and durable surgical procedure for producing prolonged pain relief in patients with medically intractable glossopharyngeal neuralgia.

Authors
Sampson, JH; Grossi, PM; Asaoka, K; Fukushima, T
MLA Citation
Sampson, JH, Grossi, PM, Asaoka, K, and Fukushima, T. "Microvascular decompression for glossopharyngeal neuralgia: long-term effectiveness and complication avoidance." Neurosurgery 54.4 (April 2004): 884-889.
PMID
15046654
Source
pubmed
Published In
Neurosurgery
Volume
54
Issue
4
Publish Date
2004
Start Page
884
End Page
889

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma.

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.

Authors
Quinn, JA; Reardon, DA; Friedman, AH; Rich, JN; Sampson, JH; Vredenburgh, J; Gururangan, S; Provenzale, JM; Walker, A; Schweitzer, H; Bigner, DD; Tourt-Uhlig, S; Herndon, JE; Affronti, ML; Jackson, S; Allen, D; Ziegler, K; Bohlin, C; Lentz, C; Friedman, HS
MLA Citation
Quinn, JA, Reardon, DA, Friedman, AH, Rich, JN, Sampson, JH, Vredenburgh, J, Gururangan, S, Provenzale, JM, Walker, A, Schweitzer, H, Bigner, DD, Tourt-Uhlig, S, Herndon, JE, Affronti, ML, Jackson, S, Allen, D, Ziegler, K, Bohlin, C, Lentz, C, and Friedman, HS. "Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma." Neuro Oncol 6.2 (April 2004): 145-153.
PMID
15134629
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
2
Publish Date
2004
Start Page
145
End Page
153
DOI
10.1215/S1152851703000498

Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma.

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.

Authors
Reardon, DA; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, J; Sampson, JH; Provenzale, JM; Walker, A; Badruddoja, M; Tourt-Uhlig, S; Herndon, JE; Dowell, JM; Affronti, ML; Jackson, S; Allen, D; Ziegler, K; Silverman, S; Bohlin, C; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Quinn, JA, Rich, JN, Gururangan, S, Vredenburgh, J, Sampson, JH, Provenzale, JM, Walker, A, Badruddoja, M, Tourt-Uhlig, S, Herndon, JE, Dowell, JM, Affronti, ML, Jackson, S, Allen, D, Ziegler, K, Silverman, S, Bohlin, C, Friedman, AH, Bigner, DD, and Friedman, HS. "Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma." Neuro Oncol 6.2 (April 2004): 134-144.
PMID
15134628
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
2
Publish Date
2004
Start Page
134
End Page
144

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.

Authors
Rich, JN; Reardon, DA; Peery, T; Dowell, JM; Quinn, JA; Penne, KL; Wikstrand, CJ; Van Duyn, LB; Dancey, JE; McLendon, RE; Kao, JC; Stenzel, TT; Ahmed Rasheed, BK; Tourt-Uhlig, SE; Herndon, JE; Vredenburgh, JJ; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Reardon, DA, Peery, T, Dowell, JM, Quinn, JA, Penne, KL, Wikstrand, CJ, Van Duyn, LB, Dancey, JE, McLendon, RE, Kao, JC, Stenzel, TT, Ahmed Rasheed, BK, Tourt-Uhlig, SE, Herndon, JE, Vredenburgh, JJ, Sampson, JH, Friedman, AH, Bigner, DD, and Friedman, HS. "Phase II trial of gefitinib in recurrent glioblastoma." J Clin Oncol 22.1 (January 1, 2004): 133-142.
PMID
14638850
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
1
Publish Date
2004
Start Page
133
End Page
142
DOI
10.1200/JCO.2004.08.110

In vitro cytotoxic activity of Thai medicinal plants used traditionally to treat cancer.

The SRB assay was used to test cytotoxicity against three human cancer cell lines and one normal cell line of 11 Thai medicinal plant species used by traditional doctors in treating cancer patients. The extraction procedures used were similar to those practised by Thai traditional doctors (ethanolic and water extracts). Extracts were tested against the human large cell lung carcinoma cell line COR-L23, the human breast adenocarcinoma cell line MCF-7 and human colon adenocarcinoma cell line LS-174T and normal human keratinocytes SVK-14. The results showed that three plants; Dioscorea membranacea Pierre ex Prain & Burkill, Dioscorea birmanica Prain & Burkill (Dioscoreaceae) and Siphonodon celastrineus Griff. (Celastraceae), exhibited high cytotoxic activity showing a certain degree of selectivity against the different cell types.

Authors
Itharat, A; Houghton, PJ; Eno Amooquaye, E; Burke, PJ; Sampson, JH; Raman, A
MLA Citation
Itharat, A, Houghton, PJ, Eno Amooquaye, E, Burke, PJ, Sampson, JH, and Raman, A. "In vitro cytotoxic activity of Thai medicinal plants used traditionally to treat cancer." Journal of ethnopharmacology 90.1 (January 2004): 33-38. (Academic Article)
Source
manual
Published In
Journal of Ethnopharmacology
Volume
90
Issue
1
Publish Date
2004
Start Page
33
End Page
38

Immunotherapy of surgical malignancies.

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

How does the immune system attack cancer?

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

Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer.

PURPOSE: The monoclonal antibody (MAb) trastuzumab (Herceptin) effectively treats HER2-overexpressing extracerebral breast neoplasms. Delivery of such macromolecule therapeutic agents to intracerebral metastases, however, is limited by the tight junctions characteristic of the cerebral vasculature. Direct intracerebral microinfusion (ICM) is a technique that bypasses this blood-brain barrier and allows for a greater delivery of drugs directly into intracerebral tumors. EXPERIMENTAL DESIGN: A human breast cancer cell line transfected to overexpress HER2, MCF-7/HER2-18, was transplanted into the cerebrum of athymic rats. Saline, trastuzumab, or an isotype-matched control MAb was delivered systemically or by ICM to assess toxicity and efficacy. RESULTS: No clinical or histological toxicity related to trastuzumab was evident under any of the conditions studied. Delivery of trastuzumab (2 mg/kg) i.p. led to a median survival of 26.5 days, whereas treatment with trastuzumab (2 mg/kg) by ICM increased the median survival by 96% to 52 days, with two of nine rats surviving >120 days (P = 0.009). Treatment with an isotype-matched control MAb (16 mg/kg) resulted in a median survival of 21 days, which did not differ significantly from the survival of rats treated by ICM with saline (16 days; P = 0.42). Treatment by ICM with trastuzumab (16 mg/kg) led to a median survival of 45 days, with 2 of 10 rats surviving >120 days. These results represent 181% and 114% increases in median survival over the saline and MAb controls, respectively (P < 0.001). CONCLUSION: ICM of trastuzumab is safe and superior to systemic delivery as therapy for HER2-overexpressing intracerebral neoplasms in an athymic rat model.

Authors
Grossi, PM; Ochiai, H; Archer, GE; McLendon, RE; Zalutsky, MR; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Grossi, PM, Ochiai, H, Archer, GE, McLendon, RE, Zalutsky, MR, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer." Clin Cancer Res 9.15 (November 15, 2003): 5514-5520.
PMID
14654531
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
15
Publish Date
2003
Start Page
5514
End Page
5520

Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors.

TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.

Authors
Sampson, JH; Akabani, G; Archer, GE; Bigner, DD; Berger, MS; Friedman, AH; Friedman, HS; Herndon, JE; Kunwar, S; Marcus, S; McLendon, RE; Paolino, A; Penne, K; Provenzale, J; Quinn, J; Reardon, DA; Rich, J; Stenzel, T; Tourt-Uhlig, S; Wikstrand, C; Wong, T; Williams, R; Yuan, F; Zalutsky, MR; Pastan, I
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Bigner, DD, Berger, MS, Friedman, AH, Friedman, HS, Herndon, JE, Kunwar, S, Marcus, S, McLendon, RE, Paolino, A, Penne, K, Provenzale, J, Quinn, J, Reardon, DA, Rich, J, Stenzel, T, Tourt-Uhlig, S, Wikstrand, C, Wong, T, Williams, R, Yuan, F, Zalutsky, MR, and Pastan, I. "Progress report of a Phase I study of the intracerebral microinfusion of a recombinant chimeric protein composed of transforming growth factor (TGF)-alpha and a mutated form of the Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment of malignant brain tumors." J Neurooncol 65.1 (October 2003): 27-35.
PMID
14649883
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
65
Issue
1
Publish Date
2003
Start Page
27
End Page
35

Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors.

PURPOSE: The epidermal growth factor receptor (EGFR) is often amplified and structurally rearranged in malignant gliomas and other tumors such as breast and lung, with the most common mutation being EGFRvIII. In the study described here, we tested in mouse models a vaccine consisting of a peptide encompassing the tumor-specific mutated segment of EGFRvIII (PEP-3) conjugated to keyhole limpet hemocyanin [KLH (PEP-3-KLH)]. EXPERIMENTAL DESIGN: C57BL/6J or C3H mice were vaccinated with PEP-3-KLH and subsequently challenged either s.c. or intracerebrally with a syngeneic melanoma cell line stably transfected with a murine homologue of EGFRvIII. Control mice were vaccinated with KLH. To test its effect on established tumors, C3H mice were also challenged intracerebrally and subsequently vaccinated with PEP-3-KLH. RESULTS: S.c. tumors developed in all of the C57BL/6J mice vaccinated with KLH in Freund's adjuvant, and there were no long-term survivors. Palpable tumors never developed in 70% of the PEP-3-KLH-vaccinated mice. In the C57BL/6J mice receiving the PEP-3-KLH vaccine, the tumors that did develop were significantly smaller than those in the control group (P < 0.05). PEP-3-KLH vaccination did not result in significant cytotoxic responses in standard cytotoxicity assays; however, antibody titers against PEP-3 were enhanced. The passive transfer of sera from the immunized mice to nonimmunized mice protected 31% of the mice from tumor development (P < 0.05). In vivo depletion studies showed that the effector cell population was natural killer and CD8+ T cells, and in vitro assays showed that macrophages could lyse target tumor cells with serum from the PEP-3-KLH-vaccinated mice. Peptide vaccination was also sufficiently potent to have marked efficacy against intracerebral tumors, resulting in a >173% increase in median survival time, with 80% of the C3H mice achieving long-term survival (P = 0.014). In addition, C3H mice with established intracerebral tumor that received a single treatment of PEP-3-KLH showed a 26% increase in median survival time, with 40% long-term survival (P = 0.007). CONCLUSIONS: Vaccination with an EGFRvIII-specific peptide is efficacious against both s.c. and established intracerebral tumors. The therapeutic effect of peptide vaccination may be mediated, in part, by antibody-dependent cellular cytotoxicity.

Authors
Heimberger, AB; Crotty, LE; Archer, GE; Hess, KR; Wikstrand, CJ; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Crotty, LE, Archer, GE, Hess, KR, Wikstrand, CJ, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors." Clin Cancer Res 9.11 (September 15, 2003): 4247-4254.
PMID
14519652
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
11
Publish Date
2003
Start Page
4247
End Page
4254

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

Adoptive immunotherapy for malignant glioma.

Despite remarkable advancements in imaging modalities and treatment options available to patients diagnosed with malignant brain tumors, the prognosis for those with high-grade lesions remains poor. The imprecise mechanisms of currently available treatments to manage these tumors do not spare damage to the normal surrounding brain and often result in major cognitive and motor deficits. Immunotherapy holds the promise of offering a potent, yet targeted, treatment to patients with brain tumors, with the potential to eradicate the malignant tumor cells without damaging normal tissues. The T cells of the immune system are uniquely capable of recognizing the altered protein expression patterns within tumor cells and mediating their destruction through a variety of effector mechanisms. Adoptive T-cell therapy is an attempt to harness and amplify the tumor-eradicating capacity of a patients' own T cells and then return these effectors to the patient in such a state that they effectively eliminate residual tumor. Although this approach is not new to the field of tumor immunology, new advancements in our understanding of T-cell activation and function and breakthroughs in tumor antigen discovery hold great promise for the translation of this modality into a clinical success.

Authors
Mitchell, DA; Fecci, PE; Sampson, JH
MLA Citation
Mitchell, DA, Fecci, PE, and Sampson, JH. "Adoptive immunotherapy for malignant glioma." Cancer J 9.3 (May 2003): 157-166. (Review)
PMID
12952301
Source
pubmed
Published In
Cancer Journal
Volume
9
Issue
3
Publish Date
2003
Start Page
157
End Page
166

Phase II trial of temozolomide in patients with progressive low-grade glioma.

PURPOSE: Temozolomide (Temodar; Schering-Plough Corp, Kenilworth, NJ) is an imidazole tetrazinone that undergoes chemical conversion to the active methylating agent 5-(3-methyltriazen-1yl)imidazole-4-carboximide under physiologic conditions. Previous studies have confirmed activity of Temodar in the treatment of progressive and newly diagnosed malignant gliomas. We have extended these results, and now we report results of a phase II trial of Temodar for patients with progressive, low-grade glioma. PATIENTS AND METHODS: Temodar was administered orally once a day for five consecutive days (in a fasting state) at a starting dose of 200 mg/m(2)/d. Treatment cycles were repeated every 28 days following the first daily dose of Temodar. Response criteria used a combination of magnetic resonance imaging and physical examination to evaluate activity. RESULTS: Forty-six patients with low-grade glioma have been treated to date. The objective response rate was 61% (24% complete response and 37% partial response), with an additional 35% of patients having stable disease. Median progression-free survival (PFS) was 22 months (95% confidence interval [CI], 15 to infinity months) with a 6-month PFS of 98% (95% CI, 94% to 100%) and a 12-month PFS of 76% (95% CI, 63% to 92%). Toxicity observed during the study was limited to only six patients. Three patients experienced grade 3 neutropenia, with a duration greater than 3 weeks in one patient, and two patients experienced grade 3 thrombocytopenia. One patient experienced > or = grade 4 toxicity, with intracerebral hemorrhage, neutropenia, thrombocytopenia, sepsis, and death. CONCLUSION: Initial results indicate that Temodar may be active in the treatment of low-grade glioma, and thus, further evaluation of this agent in the treatment of these tumors is warranted.

Authors
Quinn, JA; Reardon, DA; Friedman, AH; Rich, JN; Sampson, JH; Provenzale, JM; McLendon, RE; Gururangan, S; Bigner, DD; Herndon, JE; Avgeropoulos, N; Finlay, J; Tourt-Uhlig, S; Affronti, ML; Evans, B; Stafford-Fox, V; Zaknoen, S; Friedman, HS
MLA Citation
Quinn, JA, Reardon, DA, Friedman, AH, Rich, JN, Sampson, JH, Provenzale, JM, McLendon, RE, Gururangan, S, Bigner, DD, Herndon, JE, Avgeropoulos, N, Finlay, J, Tourt-Uhlig, S, Affronti, ML, Evans, B, Stafford-Fox, V, Zaknoen, S, and Friedman, HS. "Phase II trial of temozolomide in patients with progressive low-grade glioma." J Clin Oncol 21.4 (February 15, 2003): 646-651.
PMID
12586801
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
21
Issue
4
Publish Date
2003
Start Page
646
End Page
651
DOI
10.1200/JCO.2003.01.009

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

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

Clinical immunotherapy for brain tumors.

As an immunization platform for brain tumors, dendritic cells supply an impressive host of advantages. On the simplest level, they provide the safety and tumor-specificity so wanted by current therapeutic options. Yet, in addition, as the fundamental antigen-presenting cell, they circumvent many of the immunologic challenges that gliomas and the CNS proffer and that other immunotherapeutic modes fail to overcome. Directions to take now include the identification of new tumor-specific and tumor-associated antigens; the determination of the optimal dendritic cell subtype, generation, loading method, maturation state, dose, and route of delivery for immunizations; the further characterization of dendritic cells and their activities; and, potentially, the discovery of ways to pulse dendritic cells efficiently in vivo. Preclinical studies continue to play an important role in refining this form of active immunotherapy.

Authors
Fecci, PE; Sampson, JH
MLA Citation
Fecci, PE, and Sampson, JH. "Clinical immunotherapy for brain tumors." Neuroimaging Clin N Am 12.4 (November 2002): 641-664. (Review)
PMID
12687917
Source
pubmed
Published In
Neuroimaging Clinics of North America
Volume
12
Issue
4
Publish Date
2002
Start Page
641
End Page
664

Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa).

Iressa (ZD1839) is a p.o.-active, selective, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that blocks signal transduction pathways implicated in cancer cell proliferation, survival, and host-dependent processes promoting cancer growth. EGFR is up-regulated in primary malignant tumors of the central nervous system (CNS) and in many systemic tumors that metastasize to the CNS. The purpose of our study was to evaluate the efficacy and toxicity of p.o.-administered ZD1839 for the treatment of established intracerebral (i.c.) tumors expressing EGFR or the tumorigenic mutated variant EGFRvIII, which is constitutively phosphorylated. Oral administration of ZD1839 at 50 or 100 mg/kg/day for 3 weeks in athymic mice with established i.c. A431 human epidermoid carcinoma expressing EGFR increased median survival by 88% (P = 0.009) and 105% (P < 0.001), respectively. Additionally, there was no evidence of systemic or CNS toxicity. However, ZD1839 failed to inhibit either s.c. or i.c. in vivo tumor growth when tumorigenicity was conferred by EGFRvIII. Western blotting revealed that treatment with ZD1839 virtually ablated phosphorylation of EGFR Tyr-1173 in A431 tumors. However, treatment of NR6M tumors with ZD1839 only partially decreased phosphorylation of EGFRvIII Tyr-1173 while up-regulating overall expression, suggesting that EGFRvIII may not be susceptible to the same molecular mechanisms of tyrosine kinase inhibition as EGFR. In conclusion, ZD1839 is active in a brain tumor model expressing EGFR, but not EGFRvIII, as EGFR mutations may lead to relative therapeutic resistance. On the basis of these observations, we believe that clinical trials of ZD1839 against brain tumors expressing EGFR are warranted, but that special consideration should be given to tumors that coexpress EGFRvIII.

Authors
Heimberger, AB; Learn, CA; Archer, GE; McLendon, RE; Chewning, TA; Tuck, FL; Pracyk, JB; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Learn, CA, Archer, GE, McLendon, RE, Chewning, TA, Tuck, FL, Pracyk, JB, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa)." Clin Cancer Res 8.11 (November 2002): 3496-3502.
PMID
12429640
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
8
Issue
11
Publish Date
2002
Start Page
3496
End Page
3502

Viruses in the treatment of brain tumors.

The grave outlook for malignant glioma patients in spite of improvements to current modalities has ushered in new approaches to therapy. Viruses have emerged on the scene and gained attention for their ability to play essentially two roles: first, as vectors for therapeutic gene delivery and second, as engineered infectious agents capable of selectively lysing tumor cells. To date, clinical brain tumor trials using viruses for gene delivery have employed retroviral or adenoviral vectors to introduce ganciclovir susceptibility to tumors in the form of the HSV1-TK gene. Clinical oncolytic studies, on the other hand, have evaluated a conditionally replicating HSV as an antineoplastic agent. Despite some promise afforded by these trials, further studies are warranted; the investigation of additional viruses to play these roles is inevitable and is now precedented.

Authors
Fecci, PE; Gromeier, M; Sampson, JH
MLA Citation
Fecci, PE, Gromeier, M, and Sampson, JH. "Viruses in the treatment of brain tumors." Neuroimaging Clin N Am 12.4 (November 2002): 553-570. (Review)
PMID
12687911
Source
pubmed
Published In
Neuroimaging Clinics of North America
Volume
12
Issue
4
Publish Date
2002
Start Page
553
End Page
570

Intracanalicular meningioma mimicking vestibular schwannoma.

SUMMARY: Three cases of intracanalicular meningioma mimicking vestibular schwannoma are presented. In each case, a contrast-enhancing mass filling the internal auditory canal was identified on MR images and was originally diagnosed as a vestibular schwannoma. Although it is difficult to differentiate definitively between these lesions preoperatively, imaging findings inconsistent with a diagnosis of vestibular schwannoma can be identified. Preoperative identification of intracanalicular meningiomas permits alterations in surgical planning that allow for the more complete resection of these rare tumors.

Authors
Asaoka, K; Barrs, DM; Sampson, JH; McElveen, JT; Tucci, DL; Fukushima, T
MLA Citation
Asaoka, K, Barrs, DM, Sampson, JH, McElveen, JT, Tucci, DL, and Fukushima, T. "Intracanalicular meningioma mimicking vestibular schwannoma." AJNR Am J Neuroradiol 23.9 (October 2002): 1493-1496.
PMID
12372737
Source
pubmed
Published In
American Journal of Neuroradiology
Volume
23
Issue
9
Publish Date
2002
Start Page
1493
End Page
1496

Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion.

The gene most commonly altered in human glioblastomas is the epidermalgrowth factor receptor (EGFR). We profiled transcripts induced by mutantEGFR to better understand its role in tumor progression. The pattern found suggested enhanced tumor invasion. The highly induced genes included extracellular matrix components, metalloproteases, and a serine protease. We confirmed that mutant EGFR did make glioblastoma cells both more motile and invasive using in vitro assays. Furthermore, inhibitors of EGFR (OSI-774 and Tyrphostin AG1478) selectively down-regulated these molecular effectors in glioblastoma cells, eliminating enhanced invasion.

Authors
Lal, A; Glazer, CA; Martinson, HM; Friedman, HS; Archer, GE; Sampson, JH; Riggins, GJ
MLA Citation
Lal, A, Glazer, CA, Martinson, HM, Friedman, HS, Archer, GE, Sampson, JH, and Riggins, GJ. "Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion." Cancer Res 62.12 (June 15, 2002): 3335-3339.
PMID
12067969
Source
pubmed
Published In
Cancer Research
Volume
62
Issue
12
Publish Date
2002
Start Page
3335
End Page
3339

Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma.

PURPOSE: We conducted a phase II trial of carmustine (BCNU) plus the O(6)-alkylguanine-DNA alkyltransferase inhibitor O(6)-benzylguanine (O(6)-BG) to define the activity and toxicity of this regimen in the treatment of adults with progressive or recurrent malignant glioma resistant to nitrosoureas. PATIENTS AND METHODS: Patients were treated with O(6)-BG at an intravenous dose of 120 mg/m(2) followed 1 hour later by 40 mg/m(2) of BCNU, with cycles repeated at 6-week intervals. RESULTS: Eighteen patients were treated (15 with glioblastoma multiforme, two with anaplastic astrocytoma, and one with malignant glioma). None of the 18 patients demonstrated a partial or complete response. Two patients exhibited stable disease for 12 weeks before their tumors progressed. Three patients demonstrated stable disease for 6, 12, and 18 weeks before discontinuing therapy because of hematopoietic toxicity. Twelve patients experienced reversible > or = grade 3 hematopoietic toxicity. There was no difference in half-lives (0.56 +/- 0.21 hour v 0.54 +/- 0.20 hour) or area under the curve values (4.8 +/- 1.7 microg/mL/h v 5.0 +/- 1.3 microg/mL/h) of O(6)-BG for patients receiving phenytoin and those not treated with this drug. CONCLUSION: These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks. Future use of this approach will require strategies to minimize dose-limiting toxicity of BCNU such as regional delivery or hematopoietic stem-cell protection.

Authors
Quinn, JA; Pluda, J; Dolan, ME; Delaney, S; Kaplan, R; Rich, JN; Friedman, AH; Reardon, DA; Sampson, JH; Colvin, OM; Haglund, MM; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Gururangan, S; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Pluda, J, Dolan, ME, Delaney, S, Kaplan, R, Rich, JN, Friedman, AH, Reardon, DA, Sampson, JH, Colvin, OM, Haglund, MM, Pegg, AE, Moschel, RC, McLendon, RE, Provenzale, JM, Gururangan, S, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase II trial of carmustine plus O(6)-benzylguanine for patients with nitrosourea-resistant recurrent or progressive malignant glioma." J Clin Oncol 20.9 (May 1, 2002): 2277-2283.
PMID
11980998
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
9
Publish Date
2002
Start Page
2277
End Page
2283
DOI
10.1200/JCO.2002.09.084

Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity (131)I-labeled murine antitenascin monoclonal antibody 81C6 and determine its true response rate among patients with newly diagnosed malignant glioma. PATIENTS AND METHODS: In this phase II trial, 120 mCi of (131)I-labeled murine 81C6 was injected directly into the surgically created resection cavity of 33 patients with previously untreated malignant glioma (glioblastoma multiforme [GBM], n = 27; anaplastic astrocytoma, n = 4; anaplastic oligodendroglioma, n = 2). Patients then received conventional external-beam radiotherapy followed by a year of alkylator-based chemotherapy. RESULTS: Median survival for all patients and those with GBM was 86.7 and 79.4 weeks, respectively. Eleven patients remain alive at a median follow-up of 93 weeks (range, 49 to 220 weeks). Nine patients (27%) developed reversible hematologic toxicity, and histologically confirmed, treatment-related neurologic toxicity occurred in five patients (15%). One patient (3%) required reoperation for radionecrosis. CONCLUSION: Median survival achieved with (131)I-labeled 81C6 exceeds that of historical controls treated with conventional radiotherapy and chemotherapy, even after accounting for established prognostic factors including age and Karnofsky performance status. The median survival achieved with (131)I-labeled 81C6 compares favorably with either (125)I interstitial brachy-therapy or stereotactic radiosurgery and is associated with a significantly lower rate of reoperation for radionecrosis. Our results confirm the efficacy of (131)I-labeled 81C6 for patients with newly diagnosed malignant glioma and suggest that a randomized phase III study is indicated.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; Cokgor, I; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Regalado, LV; Sampson, JH; Shafman, TD; Wikstrand, CJ; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, Cokgor, I, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Regalado, LV, Sampson, JH, Shafman, TD, Wikstrand, CJ, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas." J Clin Oncol 20.5 (March 1, 2002): 1389-1397.
PMID
11870184
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
5
Publish Date
2002
Start Page
1389
End Page
1397
DOI
10.1200/JCO.2002.20.5.1389

Generation of anti-idiotypic reagents in the EGFRvIII tumor-associated antigen system.

The use of anti-idiotype (anti-id) vaccines for immunotherapy of human cancers is attractive, as immunization with true anti-id reagents (Ab2 beta) has been shown to induce both cellular and humoral immunity, frequently when the original antigen does not, or when a state of anergy to the self-expressed tumor-associated antigen exists. The aim of this study was to investigate the potential of an anti-id vaccine approach to the glioma-associated antigen epidermal growth factor receptor variant III (EGFRvIII) for human clinical trials. By using conventional methodology, seven rat mAbs specific for the binding site of the murine anti-EGFRvIII-specific mAb Y10, as defined by the ability to inhibit the binding of mAb Y10 to EGFRvIII expressed on cells or as purified protein, were generated, and a subset (3/7) was found to be true Ab2 beta, as defined by the ability to induce the formation of antibody directed against EGFRvIII in two species (mouse and rabbit) when used as immunogen. The ability of these three Ab2 beta to elicit a protective anti-tumor response when used as a vaccine in the syngeneic, subcutaneous C57Bl/6-B16mseEGFRvIII tumor model was investigated. Following vaccination with one Ab2 beta mAb (2C7), 6/20 mice failed to develop tumor upon challenge, and 3/20 mice with outgrowing tumors exhibited dramatic regression of incipient tumors. Vaccination with a second mAb (5G8) resulted in one tumor-free survivor and one tumor regressor; vaccination with the third Ab2 beta mAb (7D3) did not confer protection, but did significantly increase the latency period until tumor outgrowth in all vaccinated recipients. The ability of Ab2 beta mAb 2C7 to induce an anti-EGFRvIII response in non-human primates was investigated by using the saponin adjuvant approved for human clinical trial, QS-21. Three of three macaques produced anti-EGFRvIII titers, as detected on EGFRvIII-expressing cells by both ELISA and fluorescence-activated cytometric analysis, following six immunizations with Ab2 beta mAb 2C7 and QS-21. The results obtained confirm that an anti-id response in the EGFRvIII antigen system can be induced in rodents, rabbits, and non-human primates, and it may prove a useful adjunct to immunotherapeutic approaches to EGFRvIII-positive gliomas, breast carcinomas, and non-small-cell lung tumors.

Authors
Wikstrand, CJ; Cole, VR; Crotty, LE; Sampson, JH; Bigner, DD
MLA Citation
Wikstrand, CJ, Cole, VR, Crotty, LE, Sampson, JH, and Bigner, DD. "Generation of anti-idiotypic reagents in the EGFRvIII tumor-associated antigen system." Cancer Immunol Immunother 50.12 (February 2002): 639-652.
PMID
11862416
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
50
Issue
12
Publish Date
2002
Start Page
639
End Page
652
DOI
10.1007/s00262-001-0243-5

Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma.

OBJECTIVE: Dendritic cells (DCs) are specialized cells of the immune system that are capable of generating potent immune responses that are active even within the "immunologically privileged" central nervous system. However, immune responses generated by DCs have also been demonstrated to produce clinically significant autoimmunity. Targeting the epidermal growth factor receptor variant III (EGFRvIII), which is a mutation specific to tumor tissue, could eliminate this risk. The purpose of this study was to demonstrate that DC-based immunizations directed solely against this tumor-specific antigen, which is commonly found on tumors that originate within or metastasize to the brain, could be efficacious. METHODS: C3H mice were vaccinated with DCs mixed with a keyhole limpet hemocyanin conjugate of the tumor-specific peptide, PEP-3, which spans the EGFRvIII mutation, or the random-sequence peptide, PEP-1, and were intracerebrally challenged with a syngeneic melanoma expressing a murine homologue of EGFRvIII. RESULTS: Systemic immunization with DCs mixed with PEP-3-keyhole limpet hemocyanin generated antigen-specific immunity. Among mice challenged with intracerebral tumors, this resulted in an approximately 600% increase in the median survival time (>300 d, P < 0.0016), relative to control values. Sixty-three percent of mice treated with DCs mixed with the tumor-specific peptide survived in the long term and 100% survived rechallenge with tumor, indicating that antitumor immunological memory was also induced. CONCLUSION: In a murine melanoma model, immunization with DCs mixed with tumor-specific peptide results in an antigen-specific immunological response that recognizes the EGFRvIII mutation, has potent antitumor efficacy against intracerebral tumors that express EGFRvIII, and results in long-lasting antitumor immunity.

Authors
Heimberger, AB; Archer, GE; Crotty, LE; McLendon, RE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, Crotty, LE, McLendon, RE, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma." Neurosurgery 50.1 (January 2002): 158-164.
PMID
11844246
Source
pubmed
Published In
Neurosurgery
Volume
50
Issue
1
Publish Date
2002
Start Page
158
End Page
164

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Authors
Gururangan, S; Cokgor, L; Rich, JN; Edwards, S; Affronti, ML; Quinn, JA; Herndon, JE; Provenzale, JM; McLendon, RE; Tourt-Uhlig, S; Sampson, JH; Stafford-Fox, V; Zaknoen, S; Early, M; Friedman, AH; Friedman, HS
MLA Citation
Gururangan, S, Cokgor, L, Rich, JN, Edwards, S, Affronti, ML, Quinn, JA, Herndon, JE, Provenzale, JM, McLendon, RE, Tourt-Uhlig, S, Sampson, JH, Stafford-Fox, V, Zaknoen, S, Early, M, Friedman, AH, and Friedman, HS. "Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas." Neuro Oncol 3.4 (October 2001): 246-250.
PMID
11584894
Source
pubmed
Published In
Neuro-Oncology
Volume
3
Issue
4
Publish Date
2001
Start Page
246
End Page
250

In vitro keratinocyte antiproliferant effect of Centella asiatica extract and triterpenoid saponins.

Psoriasis is a hyperproliferative skin disorder estimated to be present in 1-3% of most populations. Conventional therapy using corticosteroids, Vitamin D analogs and cytotoxic agents eg psoralens is associated with low success rate and many side effects. Traditional plant remedies may provide leads for new treatments. A rapid-throughput, in vitro bioassay has been utilised to examine plants for inhibitory effects on the growth of SVK-14 keratinocytes. Centella asiatica, a reputed anti-psoriatic herb, has been compared against the psoralen-containing seeds of Psoralea corylifolia and the synthetic anti-psoriatic agent dithranol (anthralin). Aqueous extracts of Psoralea corylifolia and Centella asiatica inhibited keratinocyte replication with IC50 values of 18.4 +/- 0.6 microg/ml and 209.9 +/- 9.8 mg/ml respectively prior to treatment with polyvinylpolypyrrolidone (PVPP) and 36.3 +/- 3.3 mg/ml and 238.0 +/- 2.5 mg/ml respectively after PVPP treatment of the extracts. The effect produced by C. asiatica is thus unlikely to be due to phenolic compounds. It may, however, be due to its two constituent triterpenoid glycosides madecassoside and asiaticoside which had IC50 values of 8.6 +/- 0.6 microM respectively. These values were comparable to their concentrations in the crude extract and to the IC50 of dithranol (5.1 +/- 0.4 microM). These results suggest that the potential use of C. asiatica extracts as a topical anti-psoriatic agent is worthy of further investigation.

Authors
Sampson, JH; Raman, A; Karlsen, G; Navsaria, H; Leigh, IM
MLA Citation
Sampson, JH, Raman, A, Karlsen, G, Navsaria, H, and Leigh, IM. "In vitro keratinocyte antiproliferant effect of Centella asiatica extract and triterpenoid saponins." Phytomedicine 8.3 (May 2001): 230-235.
PMID
11417919
Source
pubmed
Published In
Phytomedicine
Volume
8
Issue
3
Publish Date
2001
Start Page
230
End Page
235
DOI
10.1078/0944-7113-00032

Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: The major mechanism of resistance to alkylnitrosourea therapy involves the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT), which removes chloroethylation or methylation damage from the O(6) position of guanine. O(6)-benzylguanine (O(6)-BG) is an AGT substrate that inhibits AGT by suicide inactivation. We conducted a phase I trial of carmustine (BCNU) plus O(6)-BG to define the toxicity and maximum-tolerated dose (MTD) of BCNU in conjunction with the preadministration of O(6)-BG with recurrent or progressive malignant glioma. PATIENTS AND METHODS: Patients were treated with O(6)-BG at a dose of 100 mg/m(2) followed 1 hour later by BCNU. Cohorts of three to six patients were treated with escalating doses of BCNU, and patients were observed for at least 6 weeks before being considered assessable for toxicity. Plasma samples were collected and analyzed for O(6)-BG, 8-oxo-O(6)-BG, and 8-oxoguanine concentration. RESULTS: Twenty-three patients were treated (22 with glioblastoma multiforme and one with anaplastic astrocytoma). Four dose levels of BCNU (13.5, 27, 40, and 55 mg/m(2)) were evaluated, with the highest dose level being complicated by grade 3 or 4 thrombocytopenia and neutropenia. O(6)-BG rapidly disappeared from plasma (elimination half-life = 0. 54 +/- 0.14 hours) and was converted to a longer-lived metabolite, 8-oxo-O(6)-BG (elimination half-life = 5.6 +/- 2.7 hours) and further to 8-oxoguanine. There was no detectable O(6)-BG 5 hours after the start of the O(6)-BG infusion; however, 8-oxo-O(6)-BG and 8-oxoguanine concentrations were detected 25 hours after O(6)-BG infusion. The mean area under the concentration-time curve (AUC) of 8-oxo-O(6)-BG was 17.5 times greater than the mean AUC for O(6)-BG. CONCLUSION: These results indicate that the MTD of BCNU when given in combination with O(6)-BG at a dose of 100 mg/m(2) is 40 mg/m(2) administered at 6-week intervals. This study provides the foundation for a phase II trial of O(6)-BG plus BCNU in nitrosourea-resistant malignant glioma.

Authors
Friedman, HS; Pluda, J; Quinn, JA; Ewesuedo, RB; Long, L; Friedman, AH; Cokgor, I; Colvin, OM; Haglund, MM; Ashley, DM; Rich, JN; Sampson, J; Pegg, AE; Moschel, RC; McLendon, RE; Provenzale, JM; Stewart, ES; Tourt-Uhlig, S; Garcia-Turner, AM; Herndon, JE; Bigner, DD; Dolan, ME
MLA Citation
Friedman, HS, Pluda, J, Quinn, JA, Ewesuedo, RB, Long, L, Friedman, AH, Cokgor, I, Colvin, OM, Haglund, MM, Ashley, DM, Rich, JN, Sampson, J, Pegg, AE, Moschel, RC, McLendon, RE, Provenzale, JM, Stewart, ES, Tourt-Uhlig, S, Garcia-Turner, AM, Herndon, JE, Bigner, DD, and Dolan, ME. "Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 18.20 (October 15, 2000): 3522-3528.
PMID
11032594
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
18
Issue
20
Publish Date
2000
Start Page
3522
End Page
3528
DOI
10.1200/JCO.2000.18.20.3522

Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats.

Intracerebral microinfusion (ICM) is an innovative technique of delivering therapeutic agents throughout large portions of the brain that circumvents the blood-brain barrier, minimizes systemic toxicity, and provides a homogeneous distribution of the infused agent. Temozolomide is a novel methylating agent with proven efficacy against malignant gliomas (MGs) after systemic administration but with dose-limiting myelotoxicity. Because MGs rarely metastasize, systemic drug delivery is unnecessary. Therefore, we evaluated the efficacy and toxicity of ICM with temozolomide in an athymic rat model of human MGs. Treatment of rats by ICM with temozolomide 3 days after intracerebral challenge with D54 human MG xenograft increased median survival by 128% compared with rats treated by ICM with saline, by 113% compared with rats treated with i.p. saline, and by 100% compared with rats treated with i.p. temozolomide (P < 0.001). Delay of treatment until 9 days after tumor challenge still resulted in a 23% increase in median survival in rats treated by ICM of temozolomide compared with rats treated with i.p. temozolomide. In addition, overall, 21.7% of rats treated by ICM with temozolomide survived for > 100 days without clinical or histological evidence of tumor. The dose of temozolomide delivered by ICM in this study was limited only by drug solubility, and no neurological or systemic toxicity could be attributed to ICM with temozolomide. Therefore, ICM of temozolomide may offer significant advantages in the treatment of MGs.

Authors
Heimberger, AB; Archer, GE; McLendon, RE; Hulette, C; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, McLendon, RE, Hulette, C, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Temozolomide delivered by intracerebral microinfusion is safe and efficacious against malignant gliomas in rats." Clin Cancer Res 6.10 (October 2000): 4148-4153.
PMID
11051269
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
6
Issue
10
Publish Date
2000
Start Page
4148
End Page
4153

Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors.

The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fc receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system.

Authors
Sampson, JH; Crotty, LE; Lee, S; Archer, GE; Ashley, DM; Wikstrand, CJ; Hale, LP; Small, C; Dranoff, G; Friedman, AH; Friedman, HS; Bigner, DD
MLA Citation
Sampson, JH, Crotty, LE, Lee, S, Archer, GE, Ashley, DM, Wikstrand, CJ, Hale, LP, Small, C, Dranoff, G, Friedman, AH, Friedman, HS, and Bigner, DD. "Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors." Proc Natl Acad Sci U S A 97.13 (June 20, 2000): 7503-7508.
PMID
10852962
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
97
Issue
13
Publish Date
2000
Start Page
7503
End Page
7508
DOI
10.1073/pnas.130166597

Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma.

To evaluate the efficacy and toxicity of dendritic cell (DC) based therapy for intracerebral gliomas, we utilized a cell line derived from an astrocytoma that arose spontaneously in a VM/Dk mouse. This astrocytoma mirrors human gliomas phenotypically, morphologically and secretes transforming growth factor (TGF)-betas, immunosuppressive cytokines secreted by human gliomas. Systemic vaccination of mice with DCs pulsed with tumor homogenate followed by intracranial tumor challenge produced a > 160% increase in median survival (p = 0.016) compared with mice vaccinated with PBS or unpulsed DCs (p = 0.083). Fifty percent of mice treated with pulsed DCs survived long-term. Immunologic memory was demonstrated by survival of mice rechallenged with tumor. Both cell-mediated and humoral immunity was induced. On histological examination only focal areas of demyelination at the tumor implantation site were present. There was no evidence that autoimmune encephalomyelitis was induced by DC vaccination. Therefore, in a murine model, vaccination with DCs pulsed with glioma tumor homogenate is a safe and effective therapy against a syngeneic glioma located in the immunologically privileged central nervous system (CNS).

Authors
Heimberger, AB; Crotty, LE; Archer, GE; McLendon, RE; Friedman, A; Dranoff, G; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Crotty, LE, Archer, GE, McLendon, RE, Friedman, A, Dranoff, G, Bigner, DD, and Sampson, JH. "Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma." J Neuroimmunol 103.1 (February 1, 2000): 16-25.
PMID
10674985
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
103
Issue
1
Publish Date
2000
Start Page
16
End Page
25

Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays.

A number of plant species used in traditional medicine for the relief of pain have been selected from the medicinal and scientific literature of China, South America, Asia and West Africa. Extracts were prepared and tested in three in vitro receptor radioligand binding assays to determine whether there was an indication of biological activity, in particular their selectivity to a single receptor implicated in the mediation of pain. The three neuropeptide receptors chosen were Bradykinin (BK II), expressed in Chinese hamster ovary cells (CHO), neurokinin 1 (NK 1) expressed in astrocytoma cells, and calcitonin gene related peptide (CGRP) which were all implicated in the mediation of acute pain in the mammaliancentral nervous system. The plant species chosen to investigate were Ageratum conyzoides, Barringtonia edulis, Croton tiglium, Ipomea pes-caprae, Panax ginseng, Physostigma venenosum, Sinomenium acutum, Solidago virgaurea, Symplocos leptophylla and Typhonium giganteum. The results showed that there was a strong indication of biological activity for some of the plants which are used ethnomedicinally to treat pain, in the three in vitro receptor binding assays used, and particular plant extracts exhibited selective action to a single receptor.

Authors
Sampson, JH; Phillipson, JD; Bowery, NG; O'Neill, MJ; Houston, JG; Lewis, JA
MLA Citation
Sampson, JH, Phillipson, JD, Bowery, NG, O'Neill, MJ, Houston, JG, and Lewis, JA. "Ethnomedicinally selected plants as sources of potential analgesic compounds: indication of in vitro biological activity in receptor binding assays." Phytother Res 14.1 (February 2000): 24-29.
PMID
10641043
Source
pubmed
Published In
Phytotherapy Research
Volume
14
Issue
1
Publish Date
2000
Start Page
24
End Page
29

EGFRvIII: An oncogene deletion mutant cell surface receptor target expressed by multiple tumour types

Optimal immunotherapeutic approaches to cancer cell eradication require the specific recognition of neoplastic cells and minimal destruction of bystander, normal cells. This is especially crucial within the CNS because of the infiltrative growth pattern of primary CNS tumours. The recently defined class III variant of the epidermal growth factor receptor (EGFRvIII), which is a transmembrane, tumour-specific, altered growth factor receptor molecule not expressed in normal tissues, shows promise in preclinical studies as a mediator of multiple immunotherapeutic approaches to tumours, both CNS and systemic, that express this marker. Specific monoclonal antibodies (mAbs) and derived constructs specific for EGFRvIII have been developed and the molecular engineering and affinity maturation techniques currently available have resulted in the generation of highly specific cytostatic and cytotoxic reagents for clinical trial. In addition, the immunogenic properties of the EGFRvIII transmembrane segment have made possible several successful vaccination strategies in preclinical models. In summary, targeting of the EGFRvIII molecule by a variety of immune approaches is a promising adjunct to current therapy. © 2000 Ashley Publications Ltd.

Authors
Wikstrand, CJ; Sampson, JH; Bigner, DD
MLA Citation
Wikstrand, CJ, Sampson, JH, and Bigner, DD. "EGFRvIII: An oncogene deletion mutant cell surface receptor target expressed by multiple tumour types." Expert Opinion on Therapeutic Targets 4.4 (2000): 497-514.
Source
scival
Published In
Expert Opinion on Therapeutic Targets
Volume
4
Issue
4
Publish Date
2000
Start Page
497
End Page
514
DOI
10.1517/14728222.4.4.497

Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1.

The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.

Authors
Archer, GE; Sampson, JH; Lorimer, IA; McLendon, RE; Kuan, CT; Friedman, AH; Friedman, HS; Pastan, IH; Bigner, DD
MLA Citation
Archer, GE, Sampson, JH, Lorimer, IA, McLendon, RE, Kuan, CT, Friedman, AH, Friedman, HS, Pastan, IH, and Bigner, DD. "Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1." Clin Cancer Res 5.9 (September 1999): 2646-2652.
PMID
10499644
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
9
Publish Date
1999
Start Page
2646
End Page
2652

Treatment of neoplastic meningitis with intrathecal temozolomide.

Neoplastic meningitis (NM) results from leptomeningeal dissemination of cancers arising within the central nervous system or metastasizing to the leptomeninges from systemic neoplasms. The inability to produce therapeutic drug levels intrathecally (i.t.) with systemic administration and the minimal efficacy of chemotherapeutic agents currently available for direct i.t. use limit therapy. Temozolomide [8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4([3H])-one] is a novel methylating agent with proven activity against intraparenchymal malignant gliomas (MGs). Insolubility of the standard formulation prevents its efficacious use as an i.t. agent, however. To overcome this obstacle, we have developed a unique microcrystalline formulation of temozolomide with greatly enhanced solubility. Treatment of athymic rats bearing subarachnoid MER- human MG xenografts with four doses of i.t. microcrystalline temozolomide over a 2-week period produced a 142% increase in median survival at individual doses of 2.2 micromol (P = 0.0073) and a >367% increase in median survival at individual doses of 6.8 micromol (P = 0.0015). At the higher dose tested, three of eight rats treated developed no neurological symptoms and had no evidence of residual tumor on histological examination after treatment. Use of this microcrystalline formulation in athymic rats bearing subarachnoid MER+ human MG xenografts increased median survival >132% (P < 0.0058) at both dose levels tested. Toxicity directly attributable to the i.t. administration of microcrystalline temozolomide was exhibited in the highest dose groups only and was limited to small patchy areas of focal demyelination involving <5% of spinal cord long tracks.

Authors
Sampson, JH; Archer, GE; Villavicencio, AT; McLendon, RE; Friedman, AH; Bishop, WR; Bigner, DD; Friedman, HS
MLA Citation
Sampson, JH, Archer, GE, Villavicencio, AT, McLendon, RE, Friedman, AH, Bishop, WR, Bigner, DD, and Friedman, HS. "Treatment of neoplastic meningitis with intrathecal temozolomide." Clin Cancer Res 5.5 (May 1999): 1183-1188.
PMID
10353755
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
5
Issue
5
Publish Date
1999
Start Page
1183
End Page
1188

The Preuss Foundation Seminar on vaccine therapy for malignant primary brain tumors. February 15-17, 1998, La Jolla, Calif.

Authors
Sampson, JH
MLA Citation
Sampson, JH. "The Preuss Foundation Seminar on vaccine therapy for malignant primary brain tumors. February 15-17, 1998, La Jolla, Calif." Neuro Oncol 1.1 (January 1999): 33-42.
PMID
11550300
Source
pubmed
Published In
Neuro-Oncology
Volume
1
Issue
1
Publish Date
1999
Start Page
33
End Page
42

Monoclonal antibody therapy of human gliomas: current status and future approaches.

The development of immunotherapeutic protocols for the treatment of human CNS neoplasia over the past two decades has been impressive. Several crucial aspects have been defined, characterized, and in many cases, optimized (Wikstrand CJ, Zalutsky MR, Bigner DD: In: Liau LM, Bigner DD (eds) Brain Tumor Immunotherapy. Humana Press (in press), 2000). Specific Mabs or constructs reacting with targetable antigens are currently available and in clinical trial. In addition, additional antigens currently under study (angiogenesis-related markers, developmentally associated antigens for medulloblastoma such as L1, and the identification of new targets by SAGE, just in its infancy, will provide a veritable library of available targets for therapy. The molecular engineering and affinity maturation techniques being applied to Mab fragment optimization have already been rapidly effective in generating a variety of Mab constructs of appropriate affinity for clinical trial; as new targets are defined, and experience is accrued with the various constructs currently and prospectively available, the optimal targeting of a multitude of antigens will be possible.

Authors
Wikstrand, CJ; Cokgor, I; Sampson, JH; Bigner, DD
MLA Citation
Wikstrand, CJ, Cokgor, I, Sampson, JH, and Bigner, DD. "Monoclonal antibody therapy of human gliomas: current status and future approaches." Cancer Metastasis Rev 18.4 (1999): 451-464. (Review)
PMID
10855788
Source
pubmed
Published In
Cancer and Metastasis Reviews
Volume
18
Issue
4
Publish Date
1999
Start Page
451
End Page
464

Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats.

The current study was designed to evaluate the toxicity and activity of Spartaject Busulfan, a microcrystalline preparation of busulfan, following its intrathecal administration into a nude rat model of human neoplastic meningitis. Animals were treated through permanent indwelling subarachnoid catheters. Human glioma D-456 MG growing in the subarachnoid space was treated with 8.1 micromol of intrathecal Spartaject Busulfan. Single-dose therapy was also subsequently compared with 4 doses of 8.1 and 2.0 micromol busulfan, respectively, against D-456 MG neoplastic meningitis. Additional experiments evaluated a saline control versus 8.1 micromol x 1, 6.2 micromol x 4 and 4.1 micromol x 4, respectively, against D-456 MG. A single dose of 8.1 micromol of intrathecal Spartaject Busulfan resulted in an increase in median survival of 61.7% compared with the saline control. In experiment 2, all busulfan treatments showed increases in median survival of 142.8% (8.1 micromol x 1), 52.3% (2.0 micromol x 4), and 23% (8.1 micromol x 4) (p < 0.001 for all groups) compared with the saline control. These results suggest that a narrow therapeutic dose range for both toxicity and activity has been defined for intrathecal busulfan in the treatment of human neoplastic meningitis in athymic nude rats. Although busulfan has only limited activity against solid tumors, the high doses achievable in the CSF following intrathecal administration coupled with the steep dose-response relationships of alkylating agents, provide rationale for further evaluation of this agent.

Authors
Archer, GE; Sampson, JH; McLendon, RE; Friedman, AH; Colvin, OM; Rose, M; Sands, H; McCullough, W; Fuchs, HE; Bigner, DD; Friedman, HS
MLA Citation
Archer, GE, Sampson, JH, McLendon, RE, Friedman, AH, Colvin, OM, Rose, M, Sands, H, McCullough, W, Fuchs, HE, Bigner, DD, and Friedman, HS. "Intrathecal busulfan treatment of human neoplastic meningitis in athymic nude rats." J Neurooncol 44.3 (1999): 233-241.
PMID
10720203
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
44
Issue
3
Publish Date
1999
Start Page
233
End Page
241

The Preuss Foundation Seminar on vaccine therapy for malignant primary brain tumors

Authors
Sampson, JH
MLA Citation
Sampson, JH. "The Preuss Foundation Seminar on vaccine therapy for malignant primary brain tumors." Neuro-Oncology 1.1 (1999): 33-42.
Source
scival
Published In
Neuro-Oncology
Volume
1
Issue
1
Publish Date
1999
Start Page
33
End Page
42

Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVES: To describe the methods and results of a standardized system for clinical endpoint determination for defining and reviewing endpoints in clinical trials for HIV-infected individuals. DESIGN: A system was developed utilizing standard definitions for the 24 diagnoses or clinical events that serve as trial endpoints and together define the combined endpoint 'progression of HIV disease. A common set of case report forms were used for all trials. Thus, an event of Pneumocystis carinii pneumonia (PCP), for example, for a subject co-enrolled in an antiretroviral trial and a PCP prophylaxis trial was only reported once. METHODS: A central committee was established to define clinical events and review endpoints across all studies. Events were classified according to established criteria for confirmed, probable and possible levels of certainty. RESULTS: This report describes the methods used to ascertain and review endpoints, and summarized 2299 clinical events for 8097 subjects enrolled in one or more of nine clinical trials. Data on the diagnostic certainty of events and agreement between site clinicians and the endpoint committee are presented. CONCLUSIONS: Uniform classification of endpoints across AIDS clinical trials can be accomplished by multicenter, multitrial organizations with standardized definitions and review of endpoint documentation. Our experience suggests that nurse coordinators reviewing all submitted endpoints for every trial are warranted and the need for external review by a clinical events committee may depend on the type of trial conducted.

Authors
Green, LA; Rhame, FS; Price, RW; Perlman, DC; Capps, LG; Sampson, JH; Deyton, LR; Schnittman, SM; Fisher, EJ; Bartsch, GE; Krum, EA; Neaton, JD
MLA Citation
Green, LA, Rhame, FS, Price, RW, Perlman, DC, Capps, LG, Sampson, JH, Deyton, LR, Schnittman, SM, Fisher, EJ, Bartsch, GE, Krum, EA, and Neaton, JD. "Experience with a cross-study endpoint review committee for AIDS clinical trials. Terry Beirn Community Programs for Clinical Research on AIDS." AIDS 12.15 (October 22, 1998): 1983-1990.
PMID
9814866
Source
pubmed
Published In
AIDS
Volume
12
Issue
15
Publish Date
1998
Start Page
1983
End Page
1990

Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model.

We have previously reported that local secretion of either TNF-alpha or TGF beta1 by intracerebral SMA-560 malignant glioma tumor cells can reduce or eliminate tumor growth in mice. However, the use of TNF-alpha, while improving the overall survival of tumor bearing animals, was associated with early toxic deaths due to cerebral edema. In the present study, we demonstrate that TNF-alpha induces apoptosis of the SMA 560 cell line, as does TGF beta1, and that these two cytokines act in an additive fashion to enhance apoptosis and thus, to inhibit SMA 560 cell growth in vitro. Next, we show that the production of TGF beta1 when added to TNF-alpha production by central nervous system tumors in vivo abrogates any early deaths seen due to TNF-alpha toxicity and leads to a larger percentage of animals surviving CNS tumor challenge. Finally, we demonstrate that the production of TGF beta1 by tumor cells is associated with the abolition of tumor-associated cerebral edema in both TNF-alpha and in non-TNF-alpha producing tumors. These results are important for the development of effective and less toxic therapies for brain tumors, as well as for examining the pathogenesis of tumor-related cerebral edema.

Authors
Ashley, DM; Sampson, JH; Archer, GE; Hale, LP; Bigner, DD
MLA Citation
Ashley, DM, Sampson, JH, Archer, GE, Hale, LP, and Bigner, DD. "Local production of TGF beta1 inhibits cerebral edema, enhances TNF-alpha induced apoptosis and improves survival in a murine glioma model." J Neuroimmunol 86.1 (June 1, 1998): 46-52.
PMID
9655471
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
86
Issue
1
Publish Date
1998
Start Page
46
End Page
52

A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. Terry Beirn Community Programs for Clinical Research on AIDS.

OBJECTIVE: Evaluate safety and efficacy of oral ganciclovir (GCV) for preventing cytomegalovirus (CMV) disease in HIV-infected persons at high risk for CMV disease. DESIGN: Double-blind, placebo-controlled, randomized clinical trial in primary care clinics and private practice offices specializing in the care of people with HIV. Interventions were oral GCV (1000 mg three times/day) or placebo. Protocol amendment allowed switch to open-label oral GCV. Main outcome measures were confirmed CMV retinal or gastrointestinal mucosal disease, and death. The study enrolled 994 people co-infected with CMV and HIV, with at least one CD4 count recorded < 100 x 10(6) cells/l. RESULTS: At study completion (15 months median follow-up), CMV event rates in the oral GCV and control groups were 13.1 and 14.6 per 100 person years, respectively, a hazard ratio (HR) of 0.92 [95% confidence interval (CI), 0.65-1.27; P = 0.6]. At protocol amendment event rates were 12.7 and 15.0, respectively (HR, 0.85; 95% CI, 0.56-1.30; P = 0.45). At study completion, event rates for death were 26.6 and 32.0 (HR, 0.84; P = 0.09), and at protocol amendment were 18.9 and 19.6 (HR, 0.95; P = 0.78), respectively. At protocol amendment for the CMV endpoint, the oral GCV treatment effect was associated with baseline use of didanosine (ddI). For patients taking ddI at randomization, HR was 7.48 (P = 0.02). For patients not taking ddI, HR was 0.62 (P = 0.04). These HR were statistically different (P = 0.0006). CONCLUSIONS: In our study, 3 g/day oral GCV did not significantly reduce CMV disease incidence, but there was a suggestion of a death-rate reduction. Furthermore, results suggest that oral GVC decreased risk of CMV disease in patients not prescribed ddI, and increased risk in those prescribed ddI. For the CMV endpoint, our study differs markedly from the only similar study, although for the death endpoint, a combined analysis of studies indicated significant reduction in death rate.

Authors
Brosgart, CL; Louis, TA; Hillman, DW; Craig, CP; Alston, B; Fisher, E; Abrams, DI; Luskin-Hawk, RL; Sampson, JH; Ward, DJ; Thompson, MA; Torres, RA
MLA Citation
Brosgart, CL, Louis, TA, Hillman, DW, Craig, CP, Alston, B, Fisher, E, Abrams, DI, Luskin-Hawk, RL, Sampson, JH, Ward, DJ, Thompson, MA, and Torres, RA. "A randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of cytomegalovirus disease in HIV-infected individuals. Terry Beirn Community Programs for Clinical Research on AIDS." AIDS 12.3 (February 12, 1998): 269-277.
PMID
9517989
Source
pubmed
Published In
AIDS
Volume
12
Issue
3
Publish Date
1998
Start Page
269
End Page
277

Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma.

UNLABELLED: Brain metastases are a common and devastating complication in patients with malignant melanoma. Therapeutic options for these patients are limited, and the prognosis is usually poor. OBJECT: A retrospective review of 6953 patients with melanoma treated at a single institution was undertaken to identify demographic factors associated with the development of clinically significant brain metastases in 702 of these patients and to determine the factors influencing the prognosis of this population to permit more informed recommendations regarding surgical therapy. METHODS: Factors found to be associated with the development of brain metastases included male gender, primary lesions located on mucosal surfaces or on the skin of the trunk or head and neck, thick or ulcerated primary lesions, and histological findings of acral lentiginous or nodular lesions. The overall median survival time of all patients with brain metastases was 113.2 days, and these metastases contributed to the death of 94.5% of the patients in this group. Patients with primary lesions located in the head or neck region had a significantly shorter survival time relative to other patients with brain metastases, whereas patients with a single brain metastasis, patients without lung or multiple other visceral metastases, and patients whose initial presentation with melanoma included a brain metastasis had a significantly better prognosis. The small group of patients who survived for more than 3 years was characterized by the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease. CONCLUSIONS: Although most patients with brain metastases resulting from melanoma have a dismal prognosis, some who are likely to survive for longer periods can be identified. In these patients surgical resection can significantly prolong meaningful survival. The decision to recommend surgery should be based primarily on the resectability of the brain metastases and on the status and number of other organs with metastatic lesions.

Authors
Sampson, JH; Carter, JH; Friedman, AH; Seigler, HF
MLA Citation
Sampson, JH, Carter, JH, Friedman, AH, and Seigler, HF. "Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma." J Neurosurg 88.1 (January 1998): 11-20.
PMID
9420067
Source
pubmed
Published In
Journal of neurosurgery
Volume
88
Issue
1
Publish Date
1998
Start Page
11
End Page
20
DOI
10.3171/jns.1998.88.1.0011

Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion.

OBJECTIVE: The promise of immunotherapies developed against brain tumors in animal models has not been realized in human clinical trials. This may be because of the routine use of rodent tumors artificially induced by chemicals or viruses that do not accurately portray the intrinsic qualities of spontaneously arising human tumors and that often fail to incorporate the role of immunosuppressants, such as transforming growth factor-beta, that are secreted by human gliomas. From an astrocytoma that arose spontaneously in inbred VM/Dk mice, we have characterized a highly tumorigenic spontaneous murine astrocytoma cell line (SMA-560) that retains features of glial differentiation and naturally produces high levels of biologically active transforming growth factor-beta. We have used this model to determine whether cytokine production by tumor cells will inhibit intracerebral astrocytoma growth. METHODS: Packaging cell lines producing replication-incompetent retroviral vectors were used to transfect the SMA-560 cell line in vitro with the genes encoding the murine cytokines interleukin (IL)-2, IL-3, IL-4, IL-6, tumor necrosis factor-alpha, gamma-interferon, or granulocyte-macrophage colony-stimulating factor or the costimulatory molecule B7.1 (CD80). RESULTS: Mice challenged intracerebrally with 5000 untransfected SMA-560 cells all succumbed to tumor within 30 days, with a median survival of 25 days. In contrast, mice challenged with SMA-560 cells producing IL-2, IL-4, or tumor necrosis factor-alpha each had a more than 400% increase in median survival (P < 0.0001). In these groups, 78.3% (18 of 23 mice), 66.7% (10 of 15 mice), and 60% (6 of 10 mice) of the mice, respectively, remained alive without evidence of tumor for longer than 100 days after the initial tumor challenge. All other cytokines tested and the expression of B7.1 failed to result in an increase in median survival. CONCLUSION: Using a spontaneous astrocytoma model in an inbred mouse strain, we have shown that cytokine production by glial tumors can abrogate their tumorigenicity in vivo despite production of transforming growth factor-beta. These results predict that approaches directed at cytokine production within intracerebral astrocytomas may be efficacious in human trials and that the "immunological privilege" of the brain may not be absolute under such conditions.

Authors
Sampson, JH; Ashley, DM; Archer, GE; Fuchs, HE; Dranoff, G; Hale, LP; Bigner, DD
MLA Citation
Sampson, JH, Ashley, DM, Archer, GE, Fuchs, HE, Dranoff, G, Hale, LP, and Bigner, DD. "Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion." Neurosurgery 41.6 (December 1997): 1365-1372.
PMID
9402588
Source
pubmed
Published In
Neurosurgery
Volume
41
Issue
6
Publish Date
1997
Start Page
1365
End Page
1372

A genetically modified allogeneic cellular vaccine generates MHC class I-restricted cytotoxic responses against tumor-associated antigens and protects against CNS tumors in vivo.

An active immunotherapeutic strategy using transfected allogeneic cells for targeting the mutant epidermal growth factor receptor (EGFRvIII) on intracranial tumors was examined. Immunization with allogeneic 300.19/EGFRvIII cells induced CD8+ cytotoxic T-lymphocytes against EGFRvIII bearing syngeneic B16-F10 melanoma or 560 astrocytoma cells (H-2b), but not against allogeneic NR6 cells (H-2q) also bearing EGFRvIII significant NK cell activity was also noted in vitro. Vaccination protected against intracranial challenge with EGFRvIII-positive tumor, with 50% long term survival. In vivo depletions of effector cell subsets demonstrated the requirements for both CD8+ and CD4+ T-cells but not NK cells in producing this protective effect. These data demonstrate the generation of significant, antigen-specific and MHC class I-restricted cytotoxic immune responses which are effective against tumors present in the CNS.

Authors
Ashley, DM; Sampson, JH; Archer, GE; Batra, SK; Bigner, DD; Hale, LP
MLA Citation
Ashley, DM, Sampson, JH, Archer, GE, Batra, SK, Bigner, DD, and Hale, LP. "A genetically modified allogeneic cellular vaccine generates MHC class I-restricted cytotoxic responses against tumor-associated antigens and protects against CNS tumors in vivo." J Neuroimmunol 78.1-2 (September 1997): 34-46.
PMID
9307226
Source
pubmed
Published In
Journal of Neuroimmunology
Volume
78
Issue
1-2
Publish Date
1997
Start Page
34
End Page
46

Viruses and oncogenes in brain tumors.

Authors
Archer, GE; Sampson, JH; Bigner, DD
MLA Citation
Archer, GE, Sampson, JH, and Bigner, DD. "Viruses and oncogenes in brain tumors." J Neurovirol 3 Suppl 1 (May 1997): S76-S77. (Review)
PMID
9179801
Source
pubmed
Published In
Journal of NeuroVirology
Volume
3 Suppl 1
Publish Date
1997
Start Page
S76
End Page
S77

The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome

This randomized, open-labeled, multicenter study was designed to assess safety and pharmacokinetics of dronabinol (Marinol) tablets and megestrol acetate (Megace) micronized tablets, alone and in combination, for treatment of HIV wasting syndrome. Weight and quality of life data were also collected. Fifty-two patients (mean CD4+ count, 59 cells/μl) were randomized to one of four treatment arms: dronabinol 2.5 mg twice/day (D); megestrol acetate 750 mg/day (M750); megestrol acetate 750 mg/day+dronabinol 2.5 mg twice/day (M750+D); or megestrol acetate 250 mg/day+dronabinol 2.5 mg twice/day (M250+D). After therapy initiation, 47 patients returned for at least one visit, and 39 completed the planned 12 weeks of study visits. Occurrence of adverse events, drug discontinuation, new AIDS-defining conditions, or CD4+ T lymphocyte changes were not statistically significantly different among arms. Serious adverse events assessed as related to dronabinol included CNS events (e.g., confusion, anxiety, emotional lability, euphoria, hallucinations) and those assessed as related to megestrol acetate included dyspnea, liver enzyme changes, and hyperglycemia. The mean weight change ± SE over 12 weeks was as follows: D, -2.0 ± 1.3 kg; M750, +6.5 ± 1.1 kg; M750+D, +6.0 ± 1.0 kg; and M250+D, -0.3 ± 1.0 kg (difference among treatment arms, p = 0.0001). Pharmacokinetic parameters measured after 2 weeks of therapy for M750 were C(max) = 985 ng/ml and AUC = 22,487 ng x hr/ml, and for dronabinol and its active metabolite (HO-THC), respectively, were C(max) = 2.01; 4.61 ng/ml and AUC = 5.3; 23.7 ng x hr/ml. For megestrol acetate, but not dronabinol, there was a positive correlation at week 2 between both C(max) and AUC with each of the following: (1) weight change, (2) breakfast visual analog scale for hunger (VASH) score, and (3) dinner VASH score.

Authors
Timpone, JG; Wright, DJ; Li, N; Egorin, MJ; Enama, ME; Mayers, J; Galetto, G; Gagnon, S; Vargo, J; Chirgwin, K; Marcel, A; Cohn, D; Dudley, M; Geletko, S; Standiford, H; Cervino, K; Mushatt, DM; Greenspan, D; Powderly, W; Meyers, M; Sampson, JH; McMillan, G; Novak, R; Moreira, L
MLA Citation
Timpone, JG, Wright, DJ, Li, N, Egorin, MJ, Enama, ME, Mayers, J, Galetto, G, Gagnon, S, Vargo, J, Chirgwin, K, Marcel, A, Cohn, D, Dudley, M, Geletko, S, Standiford, H, Cervino, K, Mushatt, DM, Greenspan, D, Powderly, W, Meyers, M, Sampson, JH, McMillan, G, Novak, R, and Moreira, L. "The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome." AIDS Research and Human Retroviruses 13.4 (1997): 305-315.
PMID
9071430
Source
scival
Published In
AIDS Research and Human Retroviruses
Volume
13
Issue
4
Publish Date
1997
Start Page
305
End Page
315

The impact of human immunodeficiency virus infection on drug-resistant tuberculosis.

Infection with human immunodeficiency virus (HIV) has been associated with increased rates of single- and multidrug-resistant (MDR) tuberculosis in the New York City area. In order to examine the relationship of HIV infection to drug-resistant tuberculosis in other selected regions of the United States, we established a registry of cases of culture-proven tuberculosis. Data were collected from sites participating in an NIH-funded, community-based HIV clinical trials group. All cases of tuberculosis, regardless of HIV status, which occurred between January 1992 and June 1994 were recorded. Overall, 1,373 cases of tuberculosis were evaluated, including 425 from the New York City area, and 948 from seven other metropolitan areas. The overall prevalence of resistance to one or more drugs was 20.4%, and 5.6% of isolates were resistant to both isoniazid and rifampin (MDR). In the New York City area, HIV-infected patients were significantly more likely than persons not known to be HIV-infected, to have resistance to at least one drug (37% versus 19%) and MDR (19% versus 6%). In other geographic areas, overall drug resistance was 16%, and only 2.2% of isolates were MDR. In multiple logistic regression analyses, HIV infection was shown to be a risk factor for drug-resistant tuberculosis, independent of geographic location, history of prior therapy, age, and race. We concluded that HIV infection is associated with increased rates of resistance to antituberculosis drugs in both the New York City area and other geographic areas. MDR tuberculosis is occurring predominantly in the New York City area and is highly correlated with HIV infection.

Authors
Gordin, FM; Nelson, ET; Matts, JP; Cohn, DL; Ernst, J; Benator, D; Besch, CL; Crane, LR; Sampson, JH; Bragg, PS; El-Sadr, W
MLA Citation
Gordin, FM, Nelson, ET, Matts, JP, Cohn, DL, Ernst, J, Benator, D, Besch, CL, Crane, LR, Sampson, JH, Bragg, PS, and El-Sadr, W. "The impact of human immunodeficiency virus infection on drug-resistant tuberculosis." Am J Respir Crit Care Med 154.5 (November 1996): 1478-1483.
PMID
8912768
Source
pubmed
Published In
American journal of respiratory and critical care medicine
Volume
154
Issue
5
Publish Date
1996
Start Page
1478
End Page
1483
DOI
10.1164/ajrccm.154.5.8912768

Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system.

Vaccination with cytokine-producing tumor cells generates potent immune responses against tumors outside the central nervous system (CNS). The CNS, however, is a barrier to allograft and xenograft rejection, and established tumors within the CNS have failed to respond to other forms of systemic immunotherapy. To determine what barriers the "immunologically privileged" CNS would pose to cytokine-assisted tumor vaccines and what cytokines would be most efficacious against tumors within the CNS, we irradiated B16 murine melanoma cells producing murine interleukin 2 (IL-2), IL-3, IL-4, IL-6, gamma-interferon, or granulocyte-macrophage colony stimulating factor (GM-CSF) and used these cells as subcutaneous vaccines against tumors within the brain. Under conditions where untransfected B16 cells had no effect, cells producing IL-3, IL-6, or GM-CSF increased the survival of mice challenged with viable B16 cells in the brain. Vaccination with B16 cells producing IL-4 or gamma-interferon had no effect, and vaccination with B16 cells producing IL-2 decreased survival time. GM-CSF-producing vaccines were also able to increase survival in mice with pre-established tumors. The response elicited by GM-CSF-producing vaccines was found to be specific to tumor type and to be abrogated by depletion of CD8+ cells. Unlike the immunity generated against subcutaneous tumors by GM-CSF, however, the effector responses generated against tumors in the CNS were not dependent on CD4+ cells. These data suggest that cytokine-producing tumor cells are very potent stimulators of immunity against tumors within the CNS, but effector responses in the CNS may be different from those obtained against subcutaneous tumors.

Authors
Sampson, JH; Archer, GE; Ashley, DM; Fuchs, HE; Hale, LP; Dranoff, G; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Ashley, DM, Fuchs, HE, Hale, LP, Dranoff, G, and Bigner, DD. "Subcutaneous vaccination with irradiated, cytokine-producing tumor cells stimulates CD8+ cell-mediated immunity against tumors located in the "immunologically privileged" central nervous system." Proc Natl Acad Sci U S A 93.19 (September 17, 1996): 10399-10404.
PMID
8816812
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
93
Issue
19
Publish Date
1996
Start Page
10399
End Page
10404

Recurrence of a cerebral arteriovenous malformation after surgical excision. Case report.

Complete excision of a cerebral arteriovenous malformation (AVM) should eliminate the future risk of an associated intracranial hemorrhage. Because total removal of an AVM may be difficult to assess at the time of surgery, postoperative angiography has become the accepted standard for documenting that the removal has been accomplished. However, even angiography confirmed excision of an AVM does not completely ensure against rebleeding. Regrowth of an AVM with subsequent hemorrhage can occur. This has been documented in children and is attributed to forces acting on the immature vasculature of these younger patients. The authors report the case of an older patient whose AVM recurred when he was 28 years of age, despite an angiography proven complete excision, and emphasize that, even in adults, angiography documentation of total removal does not always eliminate the risk of reformation of an AVM.

Authors
Gabriel, EM; Sampson, JH; Wilkins, RH
MLA Citation
Gabriel, EM, Sampson, JH, and Wilkins, RH. "Recurrence of a cerebral arteriovenous malformation after surgical excision. Case report." J Neurosurg 84.5 (May 1996): 879-882.
PMID
8622165
Source
pubmed
Published In
Journal of neurosurgery
Volume
84
Issue
5
Publish Date
1996
Start Page
879
End Page
882
DOI
10.3171/jns.1996.84.5.0879

Glomus jugulare tumor metastatic to the sacrum after high-dose radiation therapy: case report.

A 47-year-old woman with left ear pain and hearing loss was diagnosed with a glomus jugulare tumor for which she received radiation therapy as the primary treatment. Over a period of 20 years, she developed temporal bone necrosis, brain stem calcifications, local tumor recurrence, and eventually metastases to her lungs and sacrum. This case underscores the often indolent nature of glomus jugulare tumors, the late sequelae of radiation therapy for benign intracranial tumors, and the potential of these tumors to metastasize. This patient's history suggests that aggressive surgical resection should be considered early for such tumors, particularly because radiation treatment does not ablate the tumor. This is only the second reported case of a glomus jugulare tumor metastatic to the sacrum.

Authors
Gabriel, EM; Sampson, JH; Dodd, LG; Turner, DA
MLA Citation
Gabriel, EM, Sampson, JH, Dodd, LG, and Turner, DA. "Glomus jugulare tumor metastatic to the sacrum after high-dose radiation therapy: case report." Neurosurgery 37.5 (November 1995): 1001-1005.
PMID
8559322
Source
pubmed
Published In
Neurosurgery
Volume
37
Issue
5
Publish Date
1995
Start Page
1001
End Page
1005

Metastatic melanoma to the spine. Demographics, risk factors, and prognosis in 114 patients.

STUDY DESIGN: One-hundred-fourteen patients with metastatic melanoma of the spine were retrospectively reviewed. OBJECTIVE: The goal was to define the demographics, risk factors, and prognosis for this population. SUMMARY OF BACKGROUND DATA: The incidence of melanoma is increasing faster than any other cancer. Therefore, orthopedic and neurologic surgeons will be increasingly confronted by patients with spinal metastases from melanoma. However, the demographics, risk factors, and prognosis remain unclear. METHODS: From 7010 consecutive patients with melanoma, 114 were identified with clinically or radiographically evident spinal metastases. A comparison was made between these patients and the remainder of the population with melanoma seen at our institution using contingency table analysis with statistical significance determined by a chi-squared test. Survival data were represented by Kaplan-Meier curves, and log-rank testing was used for statistical comparisons. RESULTS: Risk factors associated with the development of these metastases included primary lesions that were ulcerated, deeper than 0.76 mm, or of Clark level II, or located on the trunk or mucosal surfaces. The median survival time for all patients was 86 days, but this was reduced in patients with more than one metastatic site in addition to the spine. CONCLUSION: The prognosis for most patients with spinal metastases from melanoma is dismal. However, patients with metastatic disease limited to the spine and one other organ may survive for a relatively prolonged time and may be candidates for surgical intervention directed toward symptomatic relief.

Authors
Spiegel, DA; Sampson, JH; Richardson, WJ; Friedman, AH; Rossitch, E; Hardaker, WT; Seigler, HF
MLA Citation
Spiegel, DA, Sampson, JH, Richardson, WJ, Friedman, AH, Rossitch, E, Hardaker, WT, and Seigler, HF. "Metastatic melanoma to the spine. Demographics, risk factors, and prognosis in 114 patients." Spine (Phila Pa 1976) 20.19 (October 1, 1995): 2141-2146.
PMID
8588172
Source
pubmed
Published In
Spine
Volume
20
Issue
19
Publish Date
1995
Start Page
2141
End Page
2146

Dorsal root entry zone lesions for intractable pain after trauma to the conus medullaris and cauda equina.

This review was undertaken to determine the efficacy of using dorsal root entry zone (DREZ) lesions to treat intractable pain caused by trauma to the conus medullaris and cauda equina. Traumatic lesions of this area are unique in that both the spinal cord and the peripheral nerve roots are injured. Although DREZ lesions have been shown to relieve pain of spinal cord origin in many patients, they have been shown not to relieve pain of peripheral nerve origin. Therefore, 39 patients with trauma to the conus medullaris and cauda equina who underwent DREZ lesioning for intractable pain were reviewed retrospectively. The results of this review demonstrate the efficacy of DREZ lesions in these patients. At a mean follow-up period of 3.0 years, 54% of patients were pain-free without medications, and 20% required only nonnarcotic analgesic drugs for pain that no longer interfered with their daily activities. Better outcomes were noted in patients with an incomplete neurological deficit, with pain having an "electrical" character, and with injuries due to blunt trauma. Operative complications included weakness (four patients), bladder or sexual dysfunction (three), cerebrospinal fluid leak (two), and wound infection (two), but overall, 79.5% of patients (31 of 39) were without serious complications. Complications were limited to patients with prior tissue damage at the surgical exploration site and were most prevalent in patients who underwent bilateral DREZ lesions. In conclusion, this preliminary report suggests that DREZ lesions may be useful in combating intractable pain from traumatic injuries to the conus medullaris and cauda equina, with some risk to neurological function that may be acceptable in this group of patients.

Authors
Sampson, JH; Cashman, RE; Nashold, BS; Friedman, AH
MLA Citation
Sampson, JH, Cashman, RE, Nashold, BS, and Friedman, AH. "Dorsal root entry zone lesions for intractable pain after trauma to the conus medullaris and cauda equina." J Neurosurg 82.1 (January 1995): 28-34.
PMID
7815130
Source
pubmed
Published In
Journal of neurosurgery
Volume
82
Issue
1
Publish Date
1995
Start Page
28
End Page
34
DOI
10.3171/jns.1995.82.1.0028

On being poor with HIV.

Authors
Sampson, JH; Neaton, J
MLA Citation
Sampson, JH, and Neaton, J. "On being poor with HIV." Lancet 344.8930 (October 22, 1994): 1100-1101.
PMID
7934488
Source
pubmed
Published In
The Lancet
Volume
344
Issue
8930
Publish Date
1994
Start Page
1100
End Page
1101

Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group.

OBJECTIVE: To test the hypothesis that the therapeutic success rate of oral atovaquone is not worse than that of intravenous pentamidine in the primary treatment of mild and moderate Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome and to detect differences in the toxicity rates of the two treatments. DESIGN: Patients were randomly assigned to receive 21 days of open-label therapy with either atovaquone, 750 mg orally with meals three times daily, or intravenous pentamidine, 3 to 4 mg per kg body weight once daily. SETTING: Multicenter study including university and community treatment facilities. PATIENTS: Patients with human immunodeficiency virus infection and clinical presentations consistent with mild or moderate P. carinii pneumonia were eligible. For efficacy and safety analyses, patients with histologically confirmed P. carinii pneumonia were emphasized. MEASUREMENTS: Patients were monitored by clinical and laboratory evaluations for therapeutic efficacy and adverse events during the acute treatment phase and for 8 weeks after therapy was discontinued. RESULTS: As initial therapy for a histologically confirmed episode of P. carinii pneumonia, 56 patients received atovaquone and 53 received pentamidine. More patients were successfully treated with atovaquone (57%) than with pentamidine (40%), a difference of 17% (95% CI, -3% to 38%; P = 0.085), but more patients failed to respond to atovaquone (29%) than to pentamidine (17%), a difference of 12% (CI, -6% to 29%; P = 0.18). Discontinuation of original therapy because of treatment-limiting adverse events was more frequent in the pentamidine group (36%) than in the atovaquone group (4%) (difference, -32%; CI, -48% to -17%; P < 0.001). Nine patients in each treatment group died during the study. CONCLUSIONS: Oral atovaquone and intravenous pentamidine have similar rates for successful treatment of mild and moderate P. carinii pneumonia, but atovaquone has significantly fewer treatment-limiting adverse events.

Authors
Dohn, MN; Weinberg, WG; Torres, RA; Follansbee, SE; Caldwell, PT; Scott, JD; Gathe, JC; Haghighat, DP; Sampson, JH; Spotkov, J; Deresinski, SC; Meyer, RD; Lancaster, DJ
MLA Citation
Dohn, MN, Weinberg, WG, Torres, RA, Follansbee, SE, Caldwell, PT, Scott, JD, Gathe, JC, Haghighat, DP, Sampson, JH, Spotkov, J, Deresinski, SC, Meyer, RD, and Lancaster, DJ. "Oral atovaquone compared with intravenous pentamidine for Pneumocystis carinii pneumonia in patients with AIDS. Atovaquone Study Group." Ann Intern Med 121.3 (August 1, 1994): 174-180.
PMID
7880228
Source
pubmed
Published In
Annals of internal medicine
Volume
121
Issue
3
Publish Date
1994
Start Page
174
End Page
180

The gravitational shunt: an alternative approach to cerebrospinal fluid shunting.

Current cerebrospinal fluid shunts use complex differential pressure values to regulate drainage. Such systems are prone to overdrainage and obstruction, and thus have an unpredictable effect on intracranial pressure (ICP). The gravitational shunt (GS) introduces an alternative approach. It uses a single, simple valve to balance the pressures generated within a vertical shunt system. The ICP is then regulated by the position of the valve along the cranioabdominal shunt axis and not by the mechanical properties of the valve. Bench testing demonstrated that when using the GS (1) a linear correlation (r = 0.91, p < 0.001) exists between the ICP and the position of the valve along the vertical shunt axis, (2) positive and negative ICPs are maintained, and (3) the ICP can be predicted by an equation derived from theoretical principles. The GS uses a single, simple valve as a pressure regulator and an antisiphon device. It allows the maintenance of a normal negative ICP in the upright position without risk of over-drainage. The other benefits of this system are discussed.

Authors
Sampson, JH; Cardoso, ER
MLA Citation
Sampson, JH, and Cardoso, ER. "The gravitational shunt: an alternative approach to cerebrospinal fluid shunting." Surg Neurol 40.2 (August 1993): 112-118.
PMID
8362347
Source
pubmed
Published In
World Neurosurgery
Volume
40
Issue
2
Publish Date
1993
Start Page
112
End Page
118

Solitary eosinophilic granuloma invading the clivus of an adult: case report.

A 41-year-old white man with facial pain and diplopia was found to have an invasive lesion of the clivus. The final pathological diagnosis was eosinophilic granuloma. The patient's symptoms resolved completely after transsphenoidal resection of the lesion. The pathological and radiological diagnosis and the treatment of solitary eosinophilic granulomas are discussed.

Authors
Sampson, JH; Rossitch, E; Young, JN; Lane, KL; Friedman, AH
MLA Citation
Sampson, JH, Rossitch, E, Young, JN, Lane, KL, and Friedman, AH. "Solitary eosinophilic granuloma invading the clivus of an adult: case report." Neurosurgery 31.4 (October 1992): 755-757.
PMID
1407464
Source
pubmed
Published In
Neurosurgery
Volume
31
Issue
4
Publish Date
1992
Start Page
755
End Page
757

Facial pain due to vascular lesions of the brain stem relieved by dorsal root entry zone lesions in the nucleus caudalis. Report of two cases.

One patient with a pontine infarct due to a fusiform basilar artery aneurysm and one with an arteriovenous malformation within the tectum of the mesencephalon developed intractable facial pain. This pain was relieved in both patients by radiofrequency lesions in the dorsal root entry zone of the trigeminal nucleus caudalis.

Authors
Sampson, JH; Nashold, BS
MLA Citation
Sampson, JH, and Nashold, BS. "Facial pain due to vascular lesions of the brain stem relieved by dorsal root entry zone lesions in the nucleus caudalis. Report of two cases." J Neurosurg 77.3 (September 1992): 473-475.
PMID
1506898
Source
pubmed
Published In
Journal of neurosurgery
Volume
77
Issue
3
Publish Date
1992
Start Page
473
End Page
475
DOI
10.3171/jns.1992.77.3.0473

Initial management of pediatric head trauma.

Head injuries are the most common cause of disability and death in children. Identification of children who require specialized management following a head injury will reduce the associated morbidity and mortality. Thus, it is important to differentiate the child who can be safely observed and who will recover spontaneously from the child who will develop a progressive neurologic deficit from a treatable cause. A thorough history, a tailored neurologic examination and limited radiographic studies will assist the family physician in making this determination.

Authors
Sampson, JH; Rossitch, E; Oakes, WJ
MLA Citation
Sampson, JH, Rossitch, E, and Oakes, WJ. "Initial management of pediatric head trauma." Am Fam Physician 45.6 (June 1992): 2621-2628. (Review)
PMID
1595512
Source
pubmed
Published In
American family physician
Volume
45
Issue
6
Publish Date
1992
Start Page
2621
End Page
2628

Physician house call services for medically needy, inner-city residents.

To increase access to services, a non-profit, voluntary health agency was developed to provide on-site services to residents of hotels and night shelters in the Skid Road area of Portland, Oregon. From a hotel-based clinic site, volunteer physicians, nurses, and medical students make house calls. During the first 18 months, 1,184 evaluations were made, and 21 hotels and two shelters visited. Volunteers were well accepted by residents and served as members of case management teams. The additional benefits of such a program vis-a-vis extension of local government's mission and student education are discussed.

Authors
Reuler, JB; Bax, MJ; Sampson, JH
MLA Citation
Reuler, JB, Bax, MJ, and Sampson, JH. "Physician house call services for medically needy, inner-city residents." American journal of public health 76.9 (September 1986): 1131-1134. (Academic Article)
Source
manual
Published In
American journal of public health
Volume
76
Issue
9
Publish Date
1986
Start Page
1131
End Page
1134

Parasitic infections in asymptomatic homosexual men: cost-effective screening.

The purpose of this study was to develop a cost-effective strategy for screening for enteric protozoan infections in homosexual men without gastrointestinal symptoms suggesting infection. One hundred and one homosexual men in Portland, Oregon, each submitted at least one unpurged stool sample; 91% submitted three samples each. Of these, 27% had Entamoeba histolytica, 61% had nonpathogenic protozoa with or without E. histolytica, 36% had a nonpathogen alone, and 3% had Giardia lamblia. Protozoan infection was highly associated with the practice of anilingus (p less than 0.005). Infection with E. histolytica correlated significantly with the presence of nonpathogenic protozoa (p less than 0.005). The following screening strategy was judged to be the most cost-effective: examine one sample first; if E. histolytica is found or if the sample is negative, no further investigation is required; if a nonpathogen is found, one additional sample should be obtained. This strategy had a sensitivity for E. histolytica of 85% and a cost of $136 per case detected.

Authors
Levinson, W; Dunn, PM; Cooney, TG; Sampson, JH
MLA Citation
Levinson, W, Dunn, PM, Cooney, TG, and Sampson, JH. "Parasitic infections in asymptomatic homosexual men: cost-effective screening." Journal of general internal medicine : official journal of the Society for Research and Education in Primary Care Internal Medicine 1.3 (1986): 150-154. (Academic Article)
Source
manual
Published In
Journal of General Internal Medicine
Volume
1
Issue
3
Publish Date
1986
Start Page
150
End Page
154

Gender after artificial induction of ovulation and artificial insemination.

Several studies on artificial insemination by donor (AID) semen have suggested that the gender of infants can be influenced by treatment of the women with clomiphene citrate (CC) and by the type of semen used (fresh versus cryopreserved). We conducted a 3-year prospective clinical trial to test these hypotheses. Two groups of pregnant women were evaluated. Group I (n = 130) comprised women whose ovulation was induced by CC; group II (n = 190) comprised those who conceived during spontaneous ovulatory cycles. In a total of 320 pregnancies, 55 spontaneous abortions occurred, 23.1% in group I and 13.2% in group II (P less than or equal to 0.05). Two tubal ectopic pregnancies occurred in group I. Of the 100 and 165 pregnancies carried to term in the treated and control groups, respectively, 11% and 1.8% involved twins (P less than or equal to 0.005). When only single births were considered, group I had 46.1% males in 89 term pregnancies, and group II had 60.5% males in 162 term pregnancies. Significantly more female offspring occurred in the group treated with CC (P less than or equal to 0.05). Because it is possible that a portion of the effects observed in this study were a function of cryopreservation of the AID semen, we compared data on frozen sperm with data on fresh sperm in terms of abortion, gender, and incidence of multiple births; there were no significant differences. Fertil Steril 40:481, 1983.

Authors
Sampson, JH; Alexander, NJ; Fulgham, DL; Burry, KA
MLA Citation
Sampson, JH, Alexander, NJ, Fulgham, DL, and Burry, KA. "Gender after artificial induction of ovulation and artificial insemination." Fertility and sterility 40.4 (October 1983): 481-484. (Academic Article)
Source
manual
Published In
Fertility and Sterility
Volume
40
Issue
4
Publish Date
1983
Start Page
481
End Page
484

Pregnancy rates in patients treated for antisperm antibodies with prednisone.

Circulating antisperm antibodies are associated with decreased fertility in both men and women. Several recent reports suggest that corticosteroids suppress antibody levels and thus enhance fertility in such patients. Prednisone was given to 24 patients; 26 patients with antibodies were not so treated and served as controls. The treated group comprised five women and 19 men; the control group comprised one woman and 25 men who had equivalent levels of circulating antibodies. The drug, when given to men, did not cause changes in sperm count, motility, or normal forms, but it did cause significant reductions in levels of circulating immobilizing (P less than or equal to 0.039) and agglutinating (P less than or equal to 0.001) antisperm antibodies in both sexes. Fourteen pregnancies occurred during the 4-month posttreatment study period. Significantly more pregnancies occurred in the treated group than in the control group (11 treated patients [45%] and three controls [12%]; P less than or equal to 0.025). Of the five treated women, four conceived.

Authors
Alexander, NJ; Sampson, JH; Fulgham, DL
MLA Citation
Alexander, NJ, Sampson, JH, and Fulgham, DL. "Pregnancy rates in patients treated for antisperm antibodies with prednisone." International journal of fertility 28.2 (1983): 63-67. (Academic Article)
Source
manual
Published In
International Journal of Fertility
Volume
28
Issue
2
Publish Date
1983
Start Page
63
End Page
67

Competitive trail and endurance riding in the UK.

A description is given of trail and endurance riding in the UK as controlled by the Endurance Horse and Pony Society. Veterinary involvement and responsibility are described and measures for their satisfactory execution discussed. Opportunities and need for research into the problems arising are mentioned.

Authors
Hall Patch, PK; Orton, RG; Sampson, JH
MLA Citation
Hall Patch, PK, Orton, RG, and Sampson, JH. "Competitive trail and endurance riding in the UK." The Veterinary record 100.10 (March 1977): 192-194. (Academic Article)
Source
manual
Published In
The Veterinary record
Volume
100
Issue
10
Publish Date
1977
Start Page
192
End Page
194

Distribution and activity of lactic dehydrogenase isozymes in tissues from a hibernator and a non-hibernator.

Authors
Burlington, RF; Sampson, JH
MLA Citation
Burlington, RF, and Sampson, JH. "Distribution and activity of lactic dehydrogenase isozymes in tissues from a hibernator and a non-hibernator." Comparative biochemistry and physiology 25.1 (April 1968): 185-192. (Academic Article)
Source
manual
Published In
Comparative Biochemistry and Physiology
Volume
25
Issue
1
Publish Date
1968
Start Page
185
End Page
192

A Note on Automorphic Varieties.

Authors
Sampson, JH
MLA Citation
Sampson, JH. "A Note on Automorphic Varieties." Proceedings of the National Academy of Sciences of the United States of America 38.10 (October 1952): 895-898. (Academic Article)
Source
manual
Published In
Proceedings of the National Academy of Sciences of USA
Volume
38
Issue
10
Publish Date
1952
Start Page
895
End Page
898
Show More

Research Areas:

  • 3T3 Cells
  • Abortion
  • Academic Medical Centers
  • Adipates
  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Alcohol Oxidoreductases
  • Amino Acid Sequence
  • Angiogenesis Inhibitors
  • Antibiotics, Antineoplastic
  • Antibodies
  • Antibodies, Bispecific
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neoplasm
  • Antibody Affinity
  • Antibody Formation
  • Antibody Specificity
  • Anticonvulsants
  • Antigen Presentation
  • Antigen-Antibody Complex
  • Antigen-Presenting Cells
  • Antigens
  • Antigens, CD3
  • Antigens, CD4
  • Antigens, Differentiation
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
  • Antineoplastic Agents, Phytogenic
  • Antineoplastic Combined Chemotherapy Protocols
  • Antitubercular Agents
  • Astrocytoma
  • Ataxia
  • Benzamides
  • Benzenesulfonates
  • Biological Assay
  • Biopsy
  • Bispecific antibodies
  • Blood-Brain Barrier
  • Blotting, Western
  • Body Burden
  • Body Mass Index
  • Bone Marrow Cells
  • Brain
  • Brain Diseases
  • Brain Neoplasms
  • Breast Neoplasms
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • CHO Cells
  • Camptothecin
  • Cancer Vaccines
  • Carboplatin
  • Carcinogenicity Tests
  • Carmustine
  • Catalytic Domain
  • Catheterization
  • Catheters, Indwelling
  • Cell Culture Techniques
  • Cell Division
  • Cell Line
  • Cell Line, Tumor
  • Cell Membrane
  • Cell Movement
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Central Nervous System
  • Central Nervous System Neoplasms
  • Cerebral Cortex
  • Cerebrospinal Fluid Shunts
  • Cerebrovascular Disorders
  • Cervical Vertebrae
  • Chemokines
  • Chemoradiotherapy
  • Chemotherapy
  • Chemotherapy, Adjuvant
  • Chi-Square Distribution
  • Child
  • Child, Preschool
  • Chimera
  • Cholesterol
  • Chromatography
  • Cisplatin
  • Clinical Trials as Topic
  • Clinical Trials, Phase III as Topic
  • Cluster Analysis
  • Coculture Techniques
  • Cognition
  • Cohort Studies
  • Combined Modality Therapy
  • Complementarity Determining Regions
  • Cone-Beam Computed Tomography
  • Confidence Intervals
  • Contrast Media
  • Convection
  • Cranial Irradiation
  • Cranial Nerve Diseases
  • Cranial Nerve Neoplasms
  • Craniocerebral Trauma
  • Craniotomy
  • Culture Media, Conditioned
  • Cytochrome P-450 CYP3A
  • Cytokines
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic
  • DNA Methylation
  • DNA Modification Methylases
  • DNA Mutational Analysis
  • DNA Repair Enzymes
  • DNA Topoisomerases, Type I
  • Dacarbazine
  • Dactinomycin
  • Data Collection
  • Decanoic Acids
  • Decompression, Surgical
  • Dendritic Cells
  • Diagnosis, Differential
  • Diagnostic Imaging
  • Disease Models, Animal
  • Disease Progression
  • Disease-Free Survival
  • Dose Fractionation
  • Dose-Response Relationship, Drug
  • Dose-Response Relationship, Radiation
  • Drug Administration Routes
  • Drug Administration Schedule
  • Drug Delivery Systems
  • Drug Evaluation, Preclinical
  • Drug Implants
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Drug Therapy, Combination
  • Drugs, Chinese Herbal
  • Ear Neoplasms
  • Education, Graduate
  • Electrocoagulation
  • Electrophoresis, Gel, Two-Dimensional
  • Electrophoresis, Polyacrylamide Gel
  • Electroporation
  • Encephalomyelitis, Autoimmune, Experimental
  • Enzyme Inhibitors
  • Enzyme-Linked Immunosorbent Assay
  • Eosinophilic Granuloma
  • Epidermal Growth Factor
  • Epitopes
  • Equipment Design
  • Escherichia coli
  • Etoposide
  • Exophthalmos
  • Exosomes
  • Exotoxins
  • Facial Nerve
  • Female
  • Flow Cytometry
  • Follow-Up Studies
  • Forkhead Transcription Factors
  • Gadolinium DTPA
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Transfer Techniques
  • Genetic Engineering
  • Genetic Techniques
  • Genetic Testing
  • Genetic Therapy
  • Genetic Vectors
  • Genotype
  • Glasgow Coma Scale
  • Glioblastoma
  • Glioma
  • Glossopharyngeal Nerve Diseases
  • Goals
  • Guanine
  • HIV Infections
  • Head
  • Head and Neck Neoplasms
  • Health Care Costs
  • Health Services Accessibility
  • Hemocyanin
  • Histocompatibility Antigens Class I
  • History, 20th Century
  • History, 21st Century
  • Homeless Persons
  • Homosexuality
  • Humans
  • Hydroxyurea
  • Hypersensitivity, Delayed
  • Image Processing, Computer-Assisted
  • Imaging
  • Immune System
  • Immunity
  • Immunity, Innate
  • Immunization
  • Immunocompetence
  • Immunocompromised Host
  • Immunoenzyme Techniques
  • Immunoglobulin G
  • Immunoglobulin Idiotypes
  • Immunohistochemistry
  • Immunologic Surveillance
  • Immunomodulation
  • Immunosuppression
  • Immunosuppressive Agents
  • Immunotherapy
  • Immunotherapy, Adoptive
  • Immunotoxins
  • Indicators and Reagents
  • Individualized Medicine
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Infant
  • Infratentorial Neoplasms
  • Infusion Pumps
  • Infusion Pumps, Implantable
  • Infusions, Intra-Arterial
  • Infusions, Intravenous
  • Injections, Intradermal
  • Injections, Intralesional
  • Injections, Intravenous
  • Injections, Intraventricular
  • Injury Severity Score
  • Interferon-gamma
  • Interleukin-13
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Intraocular Pressure
  • Intraoperative Complications
  • Iodine Radioisotopes
  • Isocitrate Dehydrogenase
  • Isotope Labeling
  • Kaplan-Meier Estimate
  • Keratinocytes
  • Language
  • Linear Models
  • Liposomes
  • Lung Neoplasms
  • Lymph Nodes
  • Lymphocyte Activation
  • Lymphocyte Depletion
  • Lymphocytes
  • Lymphopenia
  • Macrophages
  • Magnetic Resonance Imaging
  • Male
  • Maximum Tolerated Dose
  • Melanoma
  • Melanoma, Experimental
  • Membrane Proteins
  • Meningeal Neoplasms
  • Meningioma
  • Meningitis
  • Methods
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Mice, Nude
  • Mice, Transgenic
  • Microcirculation
  • Microinjections
  • Microsurgery
  • Middle Aged
  • Models, Animal
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Targeted Therapy
  • Monitoring, Intraoperative
  • Monocytes
  • Movement
  • Multivariate Analysis
  • Mutagenesis, Site-Directed
  • Mutant Proteins
  • Mutation
  • Naphthoquinones
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Neoplasm, Residual
  • Neoplasms
  • Neoplasms, Experimental
  • Neoplastic Stem Cells
  • Neovascularization, Pathologic
  • Nerve Compression Syndromes
  • Nervous System Autoimmune Disease, Experimental
  • Neural Stem Cells
  • Neuroma, Acoustic
  • Neurosurgical Procedures
  • Niacinamide
  • Nitrosourea Compounds
  • North Carolina
  • O(6)-Methylguanine-DNA Methyltransferase
  • Observer Variation
  • Oligodendroglioma
  • Oligonucleotide Array Sequence Analysis
  • Oncology
  • Oncolytic Virotherapy
  • Oncolytic Viruses
  • Opportunistic Infections
  • Pain Management
  • Pain Measurement
  • Palliative Care
  • Paraganglioma
  • Paranasal Sinus Diseases
  • Paresis
  • Patient Selection
  • Peptide Fragments
  • Peptides
  • Phenylurea Compounds
  • Phosphoproteins
  • Phosphorylation
  • Phytotherapy
  • Pilot Projects
  • Piperazines
  • Plant Extracts
  • Plants, Medicinal
  • Poliomyelitis
  • Polyesters
  • Positron-Emission Tomography
  • Postoperative Complications
  • Posture
  • Poverty
  • Predictive Value of Tests
  • Preoperative Care
  • Prevalence
  • Principal Component Analysis
  • Prognosis
  • Proportional Hazards Models
  • Prospective Studies
  • Protein Engineering
  • Protein Kinase Inhibitors
  • Protein Precursors
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Proteome
  • Proteomics
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Publishing
  • Pyridines
  • Pyrimidines
  • Quality of Life
  • Quinazolines
  • RNA Viruses
  • Radiation Injuries
  • Radiation Tolerance
  • Radioimmunotherapy
  • Radioligand Assay
  • Radiometry
  • Radiopharmaceuticals
  • Radiosurgery
  • Radiotherapy
  • Radiotherapy Dosage
  • Radiotherapy Planning, Computer-Assisted
  • Radiotherapy, Adjuvant
  • Radiotherapy, High-Energy
  • Radiotherapy, Image-Guided
  • Radiotherapy, Intensity-Modulated
  • Randomized Controlled Trials as Topic
  • Receptor, Epidermal Growth Factor
  • Receptor, erbB-2
  • Receptors, Antigen, T-Cell
  • Receptors, Vascular Endothelial Growth Factor
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • Recombination, Genetic
  • Recurrence
  • Registries
  • Relative Biological Effectiveness
  • Remission Induction
  • Reoperation
  • Reproducibility of Results
  • Retinal Diseases
  • Retrospective Studies
  • Retroviridae
  • Retroviridae Infections
  • Risk Assessment
  • Risk Factors
  • Saccharomyces cerevisiae
  • Safety
  • Salvage Therapy
  • Sample Size
  • Saponins
  • Sensitivity and Specificity
  • Sequence Alignment
  • Serum Albumin, Radio-Iodinated
  • Signal Transduction
  • Single-Chain Antibodies
  • Sirolimus
  • Skin Neoplasms
  • Social Class
  • Socioeconomic Factors
  • Software
  • Solubility
  • Spinal Cord
  • Spinal Cord Injuries
  • Spinal Fusion
  • Spinal Neoplasms
  • Spleen
  • Standard of Care
  • Stereotaxic Techniques
  • Steroids
  • Subcutaneous Fat
  • Substrate Specificity
  • Supratentorial Neoplasms
  • Surface Plasmon Resonance
  • Surgical Wound Infection
  • Survival
  • Survival Analysis
  • Survival Rate
  • Swiss 3T3 Cells
  • T-Lymphocyte Subsets
  • T-Lymphocytes
  • T-Lymphocytes, Cytotoxic
  • T-Lymphocytes, Regulatory
  • Tenascin
  • Th2 Cells
  • Thiazoles
  • Thrombocytopenia
  • Time Factors
  • Tissue Distribution
  • Titrimetry
  • Tomography, Emission-Computed
  • Tomography, Emission-Computed, Single-Photon
  • Tomography, X-Ray Computed
  • Transfection
  • Transforming Growth Factor alpha
  • Transforming Growth Factor beta
  • Transplantation, Heterologous
  • Treatment
  • Treatment Failure
  • Treatment Outcome
  • Trigeminal Nerve
  • Tuberculosis, Multidrug-Resistant
  • Tuberculosis, Pulmonary
  • Tumor Burden
  • Tumor Cells, Cultured
  • Tumor Escape
  • Tumor Markers, Biological
  • Tumor Microenvironment
  • Tumor Suppressor Proteins
  • Tyrosine
  • Tyrphostins
  • United States
  • Urban Population
  • Vaccination
  • Vaccines, Subunit
  • Vascular Endothelial Growth Factor A
  • Viremia
  • Virulence Factors
  • Work Schedule Tolerance
  • Xenograft Model Antitumor Assays
  • Young Adult