Improving genetically engineered T cells for medulloblastomas

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Title: Improving genetically engineered T cells for medulloblastoma PROJECT SUMMARY/ABSTRACT The intent of this project is to develop antigen-specific T cells as an effective immunotherapy for medulloblastoma (MB), a most common pediatric brain tumor. While recent advances in MB treatment slightly improved the overall survival, the patients are left with long-term devastating side effects as a result of a treatment. The body’s natural immune defenses against cancer often fail because the cancer either does not provoke or actively inhibits immune responses. However, genetic modification of the patient’s own immune system can be used to endow T cells with improved ability to recognize and kill cancerous cells that would not otherwise respond to conventional therapies. Cancer treatments consisting of the infusion of T cells that are engineered to recognize tumor antigens, molecules present only on cancers cells, have shown dramatic success in clinical studies against leukemia. We now propose to develop such approach for MB. In our method, we will target two antigens called IL13Ra2 and B7-H3 which are present on MB cells. Next, we will improve our approach by deleting epigenetic regulators that are known to suppress T cell effector function. Finally, we will use an immunocompetent MB mouse model to ask which immune cells within brain tumor microenvironment (TME) control CAR T cell efficacy. Brain tumors are notorious for having an immunosuppressive TME, yet its effect on engineered immune cells are poorly understood. Thus, the use of mouse models with functional immune system will allow us to accurately evaluate the function and safety of engineered T cells as well as understand the brain TME. In summary, we propose to first establish CAR T cells targeting two antigens in order to improve their specificity (Aim 1). We will then improve their persistence through ablation of epigenetic programs (Aim 2). We will also perform a detailed mechanistic study to determine how epigenetic regulators control effector function of engineered CAR T cells. Finally, we will investigate if elimination of key inhibitory immune cells within the brain TME will enhance anti- tumor effects of CAR T cells (Aim 3). We expect that our proposed studies using gene engineered bi-specific CAR T cells and immunocompetent mouse model will provide mechanistic insight and superior understanding on how engineered T cells function and interact with the brain TME. We believe that such knowledge will lead not only to the creation of improved immune cell-based approaches but also to potential novel therapeutic approaches for brain tumors in the future. If our pre-clinical approach is successful, we have the resources to develop a Phase I clinical trial at our institution.