Duke SPORE in Brain Cancer
Duke University
Principal Investigator(s):
David M. Ashley, MBBS (Hon), FRACP, PhD
Francis Ali-Osman, DSc
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Neoantigen Immunotherapy in Brain Tumors Using ANTI-CD27 to Deplete Regulatory T Cells Selectively
- Project 2: “Arresting” Bone Marrow T Cell Sequestration in GBM
- Project 3: A Novel Cellular Tumor Vaccine Strategy for Mutant IDH1+ Glioma
- Administrative Core
- Biostatistics and Bioinformatics Core
- Clinical Trial Operations Core
- Biorepository, Pathology, and Immune Monitoring Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
David M. Ashley, MBBS (Hon), FRACP, PhD
Rory David Deutsch Professor of Neuro-Oncology
Director, The Preston Robert Tisch Brain Tumor Center at Duke
Director, Pediatric Neuro-Oncology
Chief, Preuss Laboratory for Brain Tumor Research
Department of Neurosurgery
203 Research Drive
Medical Sciences Research Building 1 (MSRB 1)
Durham, NC 27710
Francis Ali-Osman, DSc
Professor Emeritus in Neurosurgery
Duke University
303 Research Drive
Durham, NC 27710
Overview
Malignant primary brain tumors, like glioblastoma (GBM), are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity to systemic tissue or surrounding eloquent brain. Building on the Duke Brain Tumor Program’s longstanding focus on development, refinement, and testing of immunotherapies to treat low-grade gliomas and GBM, the Duke SPORE in Brain Cancer continues work to develop new or improve existing therapies to improve the life of patients with primary malignant brain tumors.
Innovative research proposed includes:
- studies of potent neoantigen and Cytomegalovirus vaccines in the context of regulatory T cell depletion using a novel approach targeting CD27 to overcome both host immunosuppression and antigenic heterogeneity endemic to GBM (Project 1);
- studies employing a novel therapeutic strategy to reverse the recently discovered phenomenon of T cell sequestration in patients with GBM and overcome the limitations imposed on immunotherapy by longstanding lymphopenia in this population (Project 2); and
- studies examining the mechanisms and efficacy of a novel cellular tumor vaccine strategy that uses antigen-loaded monocytes and an endogenous antigen transfer pathway to stimulate potent anti-tumor T cell responses (Project 3).
Project 1: Neoantigen Immunotherapy in Brain Tumors Using ANTI-CD27 to Deplete Regulatory T Cells Selectively
Project Co-Leaders:
John H. Sampson, MD, PhD, MHSc, MBA (Clinical Co-Leader)
Qi-Jing Li, PhD (Basic Co-Leader)
Project 1 will conduct a clinical trial to evaluate a peptide vaccine targeting Tumor-Associated Antigens (TAAs), given with an adjuvant poly-ICLC (Hiltonol). TAA has been tested previously against glioblastoma with minimal success, partly due to insufficient CD8+ T cell responses to low level antigen expression of individual epitopes. Aim 1 will evaluate the safety, identify the optimal dose and schedule, and preliminary therapeutic activity of a multi-TAA peptide vaccine targeting the EphA2, the CMV pp65 and Surviving antigens, tethered to P-30 (P30-EPS), in patients with glioblastoma. Cumulative results will provide critical data on the feasibility and immunogenicity of the conjoined multi-peptide vaccine P30-EPS. This early phase trial will inform a subsequent larger trial, potentially combining the P30-EPS multi antigen vaccine with a clinically available bi-specific antibody (CDX-527) that combines a CD27 agonist antibody (αCD27) with an anti-PD-L1 antibody (αPD-L1). CDX-527 induces greater T cell stimulation, PD-1/PD-L1 axis checkpoint blockade, and potentiate anti-tumor immune activity. Aim 2 is conducting preclinical work to determine if CDX-527 simultaneously depletes TRegs based on prior data of CD27-mediated Treg depletion and increases vaccine-induced immune responses. The combination of P30-EPS with CDX-527 is expected to improve vaccine-induced CD8+ and CD4+ T cell responses. If successful, this work will develop a therapeutic strategy for patients with glioblastoma addressing the issues of host immunosuppression and intratumoral heterogeneity.
Project 2: “Arresting” Bone Marrow T Cell Sequestration in GBM
Project Co-Leaders:
Peter Fecci, MD, PhD (Clinical Co-Leader)
Robert Lefkowitz, PhD (Basic Co-Leader)
Immunotherapies continue as an active and promising area of investigation, but clinical success has been limited by GBM’s surprisingly potent capacities for eliciting severe local and systemic immune dysfunction, including profoundly low circulating T cell counts. Building on our findings that these low counts are in part due to S1P1-mediated sequestration of T cells in the bone marrow, this project will determine how T cell sequestration varies with current GBM treatments, identify biomarkers to improve selection of GBM patients for intervention, and screen novel agents that can release T cells from the bone marrow as promising immunotherapeutic adjuncts.
Project 3: A Novel Cellular Tumor Vaccine Strategy for Mutant IDH1+ Glioma
Project Co-Leaders:
David Ashley, MD (Clinical Co-Leader)
Michael D. Gunn, MD (Basic Co-Leader)
Brain tumors typically begin as slow growing low grade gliomas (LGGs) that transform in almost all cases to a universally lethal high grade glioma (HGGs) within 10 years. Traditional therapies do not prevent the ultimate progression from LGG to HGG. This project proposes a cell-based vaccine strategy to target a mutation in isocitrate dehydrogenase 1 (IDH1) found in the vast majority of LGGs and secondary HGGs. This vaccine strategy has the potential to significantly improve outcomes in patients with mutant IDH1-expressing gliomas.
Administrative Core
Core Directors:
David M. Ashley, MBBS (Hon), FRACP, PhD
Francis Ali-Osman, DSc
The Administrative Core is responsible for organizing and supporting the research projects, Shared Resource Cores, the Developmental Research Program and the Career Enhancement Program. The Core provides leadership, coordination, oversight, infrastructure, and support personnel to facilitate administrative management; promotes integration, communication, and collaboration; ensures fiscal and regulatory compliance; and oversees data operations, scientific rigor, and research progress. By serving these functions, the Administrative Core allows SPORE investigators to focus on conducting and disseminating the translational science supported by the SPORE.
Biostatistics and Bioinformatics Core
Core Directors:
James E. Herndon, II, PhD
Kouros Owzar, PhD
This Biostatistics and Bioinformatics Core will provide biostatistical and bioinformatics expertise to support all studies in the SPORE in Brain Cancer, to ensure that reliable, reproducible results are generated that have maximal impact. The Core will provide biostatistical leadership and expertise in the study design, conduct, sample size calculations, randomization, monitoring, analysis, and reporting of clinical studies in brain cancer by collaborating at all project stages, from study design to interpretation and publication of results. In addition, Core 1 will contribute bioinformatics expertise to the conduct, analysis, and reporting of correlative studies associated with clinical trials. Finally, the Core will facilitate integration of clinical, laboratory, and correlative data generated by Projects and Cores and promote data integrity.
Clinical Trial Operations Core
Core Directors:
Annick Desjardins, MD, FRCPC
Darell D. Bigner, MD, PhD
The Clinical Trial Operations Core provides clinical leadership, infrastructure, and expertise for the proposed research and clinical trials with patients. The Core ensures the safe and efficient conduct of clinical studies and recruitment, consent and enrollment of a diverse group of subjects for biospecimen collection and clinical studies. Through these Aims, the Core provides critical oversight of the full range of clinical trial activities, including study design, protocol preparation, research staff training, patient recruitment, patient evaluation during treatment and follow-up, assessment and treatment of complications, and evaluation of patient outcomes. To ensure rigorous trial conduct, the Core maintains a full portfolio of standard operating procedures (SOPs). In addition, the Core is fully integrated with other Duke Brain SPORE components to ensure seamless research coordination.
Biorepository, Pathology, and Immune Monitoring Core
Core Directors:
Roger McLendon, PhD
Kent Weinhold, PhD
The Biorepository, Pathology, and Immune Monitoring Core provides scientific leadership as well as comprehensive and state-of-the-art biospecimen, pathologic, and immune monitoring support. The Core will:
- Provide blood and tissue distribution and tracking services, tissue diagnosis, immunohistochemical (IHC) and biobanking support to the Projects’ clinical and correlative studies.
- Provide GCLP-compliant, comprehensive Immune Monitoring of patients enrolled in the Projects’ clinical studies using standardized and validated state-of-the-art flow cytometry-based immune profiling platforms.
In addition, the Inter-SPORE consortium for immune monitoring will continue to share development and validation of new immune profiling platforms while also attempting to standardize all aspects of specimen acquisition, preparation, transport, and evaluation according to a uniform set of Standard Operating Procedures (SOPs).
Developmental Research Program
Program Directors:
Francis Ali-Osman, DSc
John H. Sampson, MD, PhD, MHSc, MBA
The Duke SPORE DRP supports promising individual or collaborative pilot research projects that have a translational potential and are likely to generate new knowledge with a high probability to impact the diagnosis, treatment and/or prevention of adult and/or pediatric brain tumors. This program typically supports established faculty or investigators who wish to further develop or refocus their careers on translational research in primary brain cancer.
Career Enhancement Program
Program Directors:
John H. Sampson, MD, PhD, MHSc, MBA
David Ashley, MD
Ann Marie Pendergast, PhD
The Career Enhancement Program (CEP) supports pilot research projects from promising new and early stage investigators with translational potential. Projects are encouraged to be broadly collaborative within Duke University, but also with other institutions, and to test novel concepts and paradigms that bring new approaches into the field and that will further expand the scope of brain tumor diagnosis, prevention, and management.