UC San Diego

Chimeric Antigen Receptor (CAR) T cell therapy is a revolutionary treatment option for cancer therapy, demonstrating widespread clinical success in treating hematological malignancies such as acute lymphoblastic leukemia and certain lymphomas. Despite its widespread success treating hematological malignancies, CAR T cells still struggle to treat solid tumors. One reason for this is the immunosuppressive tumor microenvironment. Expressed in certain tumors, Programmed Death-Ligand 1 (PD-L1) actively suppresses T cell activation and function. To both neutralize this immunoinhibitory effect and eliminate tumor cells, I used yeast display mediated directed evolution to engineer PDbody, derived from the monobody scaffold, to bind to PD-L1. I then employed PDbody as a SynNotch-gated CAR receptor to eliminate a triple-negative breast cancer model in vitro and slow tumor growth in vivo. CAR T cell therapy can also fail when tumors do not homogenously express the CAR target antigen. To combat this problem, I developed heat-inducible Cis-activated CAR (CisCAR) to allow CAR T cells to self-present their target antigen. I then used CisCAR to eliminate antigen-negative leukemic and breast cancer cells in vitro, demonstrating the universal applicability of this treatment strategy. Overall, this dissertation presents new methods that enhance CAR T cell therapy, enabling them to more effectively target a wider range of diseases.