(Provided by the applicant) Abstract: Malignant primary brain tumors account for more deaths than cancer of the kidney or melanoma and now represent the most common cause of cancer death in children and young adults. Current therapy for glioblastoma (GBM), the most common and most malignant of these tumors consists of surgical resection followed by radiation and chemotherapy, which is limited by toxicity to systemic tissues and surrounding eloquent brain. Despite aggressive therapy, these tumors remain universally fatal;therefore, it is important to develop alternate therapies fo this deadly disease. Subtle modifications to normal 'self'proteins caused by cancer are detectable in the form of surface protein, or internally processed and presented on cell surface MHC molecules. Since these changes alter the structure of otherwise normal tissues, they provide a specific target. Immunotherapy, recently shown to be effective in several Phase III clinical trials for patients with metastatic melanoma and prostate cancer, offers a specific targeted approach for the eradication of tumors. Adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells utilizes the cellular immune system to target discrete tumor antigens and destroy the diseased cells bearing them. These T cell responses can be directed by genetically engineering in new receptor molecules using gamma-retroviral or lentiviral vector systems. Genes encoding highly avid T cell receptors (TCR) or chimeric antigen receptors (CAR), which combine highly avid antibody variable regions with T cell signaling molecules, induce T cell activation upon encounter of the target antigen. Genetically TCR re-directed T cells have been extremely potent in immunotherapy against tumors and have been shown to eliminate bulky tumor in patients with metastatic melanoma, and recent clinical trials using CAR vectors targeting CD19 to treat patients with disseminated lymphoma have been safe and produced dramatic clinical responses in advanced disease. Combining CAR T cell technology to immunotherapy of GBM provides a platform to potentially eliminate this cancer in patients, without the non-specific toxicity seen in generalized therapy. GBM has several ideal antigenic targets for CARs, including the tumorigenic EGFRvIII tumor-specific mutation, and CMV antigens, found to be expressed specifically in tumor, but not surrounding normal tissues. While we propose to treat patients with GBM, this platform can readily be expanded to target antigens from other CNS cancers, such as medulloblastoma, within the Brain Tumor Center at Duke. This grant would allow for the establishment of a dedicated T cell based gene therapy facility to construct and test different CAR constructs in preclinical models and rapidly translate them into clinical trials for patients with cancer. Public Health Relevance: Current therapy for GBM, the most common and most malignant brain tumors consists of surgery, followed by radiation and chemotherapy, which causes toxicity to the patient and damage to surrounding tissues. Using genetic engineering we plan to redirect GBM patients'own T cells to target and destroy their cancer as an active immune therapy.
|Miao, Hongsheng; Choi, Bryan D; Suryadevara, Carter M et al. (2014) 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:e94281|
|Sampson, John H; Choi, Bryan D; Sanchez-Perez, Luis et al. (2014) EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin Cancer Res 20:972-84|