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Last Updated: 03/09/17

DUKE SPORE IN BRAIN CANCER

Duke University Medical Center

Principal Investigators:
John H. Sampson, MD, PhD, MBA
Francis Ali-Osman, DSc

OVERVIEW

The team behind the Duke SPORE in Brain Cancer is a group of basic scientists and translational physician-scientists with a strong collaborative history who are proposing novel approaches for treatment of low grade gliomas and glioblastoma (GBM). These treatments may also protect the brain from the harmful effects of traditional treatments or combat limitations that have been identified in other therapeutic approaches. The overall goal is to develop new or improve existing therapies that will prolong the quality and length of life for patients with malignant brain tumors. Researchers also expect to gain a better understanding of the biology of these tumors and the patient’s response to the tumor and the therapy, as well as attract new investigators to this area of research. This SPORE encompasses a series of four Projects, four supporting Cores, and Career Enhancement and Developmental Research Programs.

PROJECT 1: INTRACEREBRALLY DELIVERED EGFRVIII-TARGETED CARS FOR BRAIN TUMORS

Project Co-Leaders:
John H. Sampson, MD, PhD, MBA
Qi-Jing Li, PhD

The overall hypothesis is that T cells transduced with EGFRvIII-targeted chimeric antigen receptors (EGFRvIII-CARs) that have been delivered intracerebrally are safe and effective. The Specific Aims are to (1) confirm that intracerebral delivery of EGFRvIII-CARs does not induce local or systemic autoimmunity, (2) establish the efficacy of intracerebrally delivered CARs against established tumors with heterogeneous EGFRvIII expression, (3) determine whether abrogation of the microRNA miR-23a in EGFRvIII-CARs enhances cytotoxicity and resistance to transforming growth factor (TGF)-b mediated immunosuppression, and 4) determine the dose-limiting toxicity and maximum tolerated dose of intracerebrally injected EGFRvIII-CARs in patients with recurrent EGFRvIII positive GBM.

PROJECT 2: PEPTIDE VACCINATION TARGETING THE TUMOR-SPECIFIC IDH1 R132H MUTATION FOR BRAIN TUMORS

Project Co-Leaders:
Hai Yan, MD, PhD
John H. Sampson, MD, PhD, MBA

The hypothesis is that a peptide vaccine targeting the R132H mutation of isocitrate dehydrogenase 1 (IDH1)R132H will be an effective tumor-specific therapy for patients with IDH1R132H-positive gliomas, without antigen escape or toxicity. The Specific Aims are to (1) determine the cellular populations responding to IDH1R132H-specific peptide (PEPIDH1M) vaccination and optimize the immunogenicity and efficacy of PEPIDH1M, (2) perform all studies of a PEPIDH1M vaccine sufficient for an Investigational New Drug (IND) application to the Food and Drug Administration (FDA), (3) conduct a pilot clinical trial to assess safety and immunogenicity of PEPIDH1M in patients with histologically proven, recurrent and resectable IDH1R132H positive grade II gliomas.

PROJECT 3: DEVELOPMENT AND VALIDATION OF A STRATEGY TO IDENTIFY IMMUNOGENIC NEOANTIGENS IN GLIOBLASTOMA

Project Co-Leaders:

Michael D. Gunn, MD
Gordana Vlahovic, MD

The objectives are to develop a strategy to identify immunogenic neoantigens in individual GBM patients and validate that this strategy yields Ags that induce robust T cell responses upon immunization. The hypothesis is that a combination of bioinformatic prioritization and the identification of neoantigen peptides bound to MHC molecules will accurately identify Ags that stimulate robust anti-GBM T cell responses. Our rationale is that, while likely to be effective, a strategy for identifying immunogenic neoantigens needs to be specifically tailored to GBM patients. Our Specific Aims are to: (1) identify potentially immunogenic GBM neoepitopes via multiple alternative strategies; (2) determine which predicted neoepitopes induce T cell and anti-tumor responses in mice; (3) identify potentially immunogenic neoepitopes in human GBM patients; (4) determine which predicted neoepitopes activate patient blood and/or tumor T cells; and (5) determine if predicted neoepitopes induce T cell responses in GBM patients.

The successful completion of these studies would result in the availability of a validated means to identify immunogenic tumor neoepitopes in individual GBM patients. Such a result would markedly expand the number of tumor antigens that could be used to induce anti-GBM immune responses in individual patients, could be rapidly advanced to clinical efficacy studies, and has the potential to significantly improve outcomes in GBM patients.

PROJECT 4: ONCOLYTIC IMMUNOTHERAPY OF MALIGNANT GLIOMA

Project Co-Leaders:
Matthias Gromeier, MD
Allan H. Friedman, MD

The hypothesis is that intratumoral infusion of a recombinant oncolytic poliovirus, PSVRIPO, is cytotoxic to malignant cells and establishes a pro-inflammatory activation state that enhances immune effector function. The Specific Aims are to (1) continue clinical investigation of PVSRIPO in patients with recurrent glioblastoma (GBM), (2) document immune responses in patients with GBM receiving PVSRIPO oncolytic immunotherapy, and (3) elucidate mechanisms of poliovirus oncolytic virotherapy in a transgenic syngeneic mouse glioma model.

CORE A: ADMINISTRATIVE CORE

Core Co-Directors
John H. Sampson, MD, PhD, MBA
Francis Ali-Osman, DSc

The Administrative Core will organize and support four translational research Projects, four Cores, the Developmental Research Program, and the Career Enhancement Program. It provides leadership, infrastructure, and support personnel to facilitate administrative management; promote integration, communication, and collaboration; and ensure fiscal and regulatory compliance and an adequate patient population. Core A will also develop capabilities, oversee data operations and evaluate research progress. By serving these functions, this Core allows SPORE investigators to focus on conducting and disseminating the translational science supported by the SPORE.

CORE B: BIOSTATISTICS, INFORMATICS, AND DATA COORDINATION CORE

Core Co-Directors
James E. Herndon, II, PhD
Kouros Owzar, PhD

This Core will serve as a central resource and a supportive infrastructure for investigators involved in the Duke SPORE in Brain Cancer. The Specific Aims of this Core are: (1) to provide biostatistical leadership and expertise in the design, conduct, analysis, and reporting of Duke SPORE in Brain Cancer studies; (2) to be the SPORE data coordination center by providing secure services for electronic data acquisition, cleansing, transfer, integration, quality control, management and sharing for the Duke SPORE in Brain Cancer Projects and Cores; and (3) To develop a longitudinal brain tumor outcomes database (“datamart”) that will serve as an enduring resource for the SPORE and brain cancer research at Duke.

CORE C: CLINICAL TRIAL OPERATIONS CORE

Core Co-Directors
Annick Desjardins, MD, FRCPC
James E. Herndon, II, PhD

Core C focuses on the safe and efficient conduct of clinical studies and ensures that a diverse group of subjects are enrolled. It oversees the clinical operation of trials conducted within the SPORE, including study design and protocol preparation, patient recruitment, patient evaluation during treatment and follow-up, assessment and treatment of complications, and evaluation of patient outcomes. The Core maintains a full portfolio of standard operating procedures (SOPs) and will align them with specific study protocols. The Core is responsible for assuring that a well-trained team of clinical research staff is available to develop protocols; recruit, screen, consent, and enroll patients; conduct the clinical trials outlined in the projects; and interface with the other cores.

CORE D: BIOSPECIMEN, PATHOLOGY, AND IMMUNE MONITORING CORE

Core Co-Directors:
Roger McLendon, MD
Kent Weinhold, PhD

The mission of the Biospecimen, Pathology and Immune Monitoring Core is to maintain a tissue bank with integrated histologic and molecular diagnostic data on all stored tissues as well as an integrated Immune Monitoring Component Laboratory that will provide all immunologic assessments proposed for the pre-clinical and clinical studies comprising the four Projects of this SPORE.