Reprogramming T cell function with multiplexed genome engineering to develop next-generation immunotherapy

Adoptive cellular immunotherapy has revolutionized cancer treatment, with engineered T cells achieving remarkable success in hematologic malignancies. However, challenges such as relapse, limited efficacy in solid tumors, and the immunosuppressive tumor microenvironment (TME) remain. This proposal addresses critical gaps in the field by developing two innovative strategies: (1) Intrinsic regulations, through self-regulatable therapeutic T cells that dynamically adjust chimeric antigen receptor (CAR) expression in response to antigen stimulation, enabling precise control over T cell activity and minimizing toxicity; and (2) extrinsic regulations, developing novel protein chimeras that exploit endogenous cellular machinery to degrade immunosuppressive proteins in the TME, restoring anti-tumor immunity. By integrating these approaches, this research aims to transform cancer immunotherapy, offering safer and more effective treatments for solid tumors and other challenging malignancies. The proposed work has the potential to improve the safety and efficacy of CAR-T cell therapies, provide new insights into receptor dynamics and immune modulation, and align with the NCI’s mission to advance innovative cancer treatments.