Glioblastoma (GBM), the most common of the primary malignant brain tumors, is uniformly fatal. In contrast to current therapy, which is limited by off-target toxicity, immunotherapy promises an exquisitely precise approach, and substantial evidence indicates that, if appropriately redirected, T cells can eradicate large, well-established tumors. We have developed a bispecific antibody that effectively redirects T cells to lyse tumor cells expressing a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) and found that our molecule localizes intracranially (IC) following systemic administration, mediating specific anti-tumor immune responses that eradicate well-established and invasive IC tumors. Preclinical models designed to test BiTEs to date, however, have universally employed xenograft systems. Such models are not ideal as they (1) do not account for proper evaluation of autoimmune toxicity, (2) do not fairly assess efficacy and the impact of a potentially suppressive tumor microenvironment, and (3) do not permit evaluation of potentially beneficial endogenous host immunity. In this proposal, we will conduct experiments employing a novel syngeneic system that directly addresses the clinically relevant limitations outlined above. Additionally, unlike other macromolecules, our data suggest that BiTEs may employ a unique mechanism to penetrate the blood-brain barrier (BBB), which may ultimately increase the biodistribution of the drug at tumor sites in the brain and have far-reaching implications for other therapies where BBB physiology is relevant. We therefore include studies to further our understanding of BiTE and T-cell biodistribution and will apply this knowledge to enhance the efficacy of the BiTE platform against IC tumors. Our overall goal is to further my training as a physician-scientist pursuing a career in translational neuro-oncology research while advancing the BiTE therapeutic platform for safe, effective immunotherapy in patients with EGFRvIII-expressing GBM. The completion of these aims will provide a strong foundation in basic science research as well as exposure to processes necessary to translate an experimental therapy to the clinic.?

Public Health Relevance

With a focus on physician-scientist training, this proposal aims to advance a new antibody-based immunotherapy for the treatment of glioblastoma (GBM), the most common malignant primary brain tumor. In addition to enhancing the pool of highly trained physician-scientists, the results of this study will advance a therapeutic approach useful in treating many forms of cancer and may also offer a new method of delivering therapeutics to the central nervous system (CNS), thus improving public health and quality of life for patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA196199-01
Application #
8909984
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2015-03-01
Project End
2019-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Suryadevara, Carter M; Desai, Rupen; Abel, Melissa L et al. (2018) Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology 7:e1434464
Reap, Elizabeth A; Suryadevara, Carter M; Batich, Kristen A et al. (2018) Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma. Cancer Res 78:256-264
Gedeon, Patrick C; Schaller, Teilo H; Chitneni, Satish K et al. (2018) A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. Clin Cancer Res 24:3611-3631
Suryadevara, Carter M; Desai, Rupen; Farber, Samuel Harrison et al. (2016) 369?Chimeric Antigen Receptors Deficient in Lck Signaling Require 4-1BB Costimulation to Expand in Vivo, Resist Regulatory T-Cell Suppression, and Treat Solid Tumors in Immune-Intact Hosts. Neurosurgery 63 Suppl 1:209-10
Asciutto, Eliana K; Gedeon, Patrick C; General, Ignacio J et al. (2016) Structure and Dynamics Study of LeuT Using the Markov State Model and Perturbation Response Scanning Reveals Distinct Ion Induced Conformational States. J Phys Chem B 120:8361-8
Suryadevara, Carter M; Gedeon, Patrick C; Sanchez-Perez, Luis et al. (2015) Are BiTEs the ""missing link"" in cancer therapy? Oncoimmunology 4:e1008339