Explore Gamma delta T cell-based glioblastoma therapies

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This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Our long-term objective is to develop highly effective cellular immunotherapies for solid tumors. In response to this NOSI, we will start a new collaboration with Dr. Yi Fan to develop chimeric antigen receptor (CAR)-T cell therapy for glioblastoma (GBM). GBM is the most common and most aggressive malignant primary brain tumor in adults, with a median overall survival of about 14-18 months. GBM tumors are also generally refractory to T cell-based immunotherapies, largely due to the immune-hostile tumor microenvironment (TME) that inhibits T cell activity. Tumor-associated myeloid cells, including myeloid-derived suppressor cells (MDSCs) and macrophages, are the major source for GBM immunosuppression, but there are currently no effective approaches to eradicate these immunosuppressive cells. Adoptive T cell transfer has to date focused mainly on αβT cell therapy. Unlike αβT cells, γδT cells manifest the features of both innate and adaptive immunity. Downregulation or loss of HLA class I or β2 microglobulin which makes tumor cells undetectable to αβT cells, is unlikely to affect γδT cell recognition. For proof-of-concept, we have developed novel CARs targeting Death Receptor 5 (DR5). DR5 is highly expressed by GBM cells and MDSCs, but not by most normal cells. Our preliminary data demonstrated that DR5-CARs may significantly inhibit both MDSCs and DR5-expressing melanoma cells with little toxicity to normal cells in xenograft models. Here, we will develop a fully murine DR5-targeting CAR T system that can be used in treating syngeneic mouse GBM models with an intact immune TME. We hypothesize that DR5-CAR-γδT cells modulate TME and have robust anti-tumor activity in GBM. In Aim 1, we will evaluate the effects of DR5-CAR T cells on tumor immunity in preclinical syngeneic mouse GBM models. In Aim 2, we will test experimental therapy that combines DR5- CAR T cells with PAK4 inhibition (to enhance T cell infiltration) and/or immune checkpoint blockade (to increase T cell activity) to treat GBM in preclinical mouse models. We expect that CAR T cells targeting DR5 may eliminate MDSCs and tumor cells in GBM and reverse tumor immunosuppression in the TME to allow host immune cells to function properly. Successful completion of this project may lead to development of a new CAR T cell immunotherapy for brain tumor.