Design of a Novel Nanocarrier Technology to Drug-Load CAR T cells

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Project summary: Current treatment for Glioblastoma Multiforme (GBM), the most common malignant brain tumor in adults, involves maximal safe resection, followed by adjuvant chemoradiation. Although this treatment is life prolonging, it is never curative. Five year survival is less than 7 %1 and improved therapies are urgently needed. In this proposal, we aim to develop a new targeted therapy with reduced toxicity and increased efficacy for GBM patients by leveraging nanotechnology discoveries in our laboratory to improve adoptive cell therapy. Chimeric Antigen Receptor (CAR) T cells combine the cytolytic potency of a T cell with the tumor specificity of an antibody. Recent clinical trial experiences of CAR T cells in solid tumors have identified the immune-suppressive tumor microenvironment (TME) as a major barrier to clinical success2-4. One immune-suppressive endogenous negative regulator in GBM TME is TGFβ, which has been identified as barrier to CAR T tumor eradication. Small molecule inhibitors of the TGFβ receptor as well as TGFβ resistant CAR T cells have been developed and tested clinically, however they are limited due to systemic toxicity. Herein we propose developing a platform technology to drug-load CAR T cells with nanocarriers, thus enhancing the therapeutic window of CAR T cells, and addressing one of the major obstacles to CAR T cells in brain tumors.