(193i) Enhanced Cancer Immunotherapy By Chimeric Antigen Receptor-Modified T Cells Engineered to Secrete Checkpoint Inhibitors

Despite favorable responses of chimeric antigen receptor (CAR)-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. In an effort to evaluate the effector function and expansion capacity of CAR.αPD1-T cells in vitro, we measured the production of IFN-γ and T cell proliferation following antigen-specific stimulation. Furthermore, the antitumor efficacy of CAR.αPD1-T cells, CAR-T cells, and CAR-T cells combined with anti-PD-1 antibody was determined using a xenograft mouse model. Finally, the underlying mechanism of enhanced tumor eradication of CAR.αPD1-T cells was investigated by analyzing the expansion and functional capacity of tumor-infiltrating lymphocytes. Human anti-PD-1 CPIs secreted by CAR.αPD1-T cells efficiently bound to PD-1 and reversed the inhibitory effect of PD-1/PD-L1 interaction on T cell function. PD-1 blockade by continuously secreted anti-PD-1 prevented T cell exhaustion and significantly enhanced T cell expansion and effector function both in vitro and in vivo. In the xenograft mouse model, we demonstrated that the secretion of anti-PD-1 enhanced the antitumor activity of CAR-T cells and prolonged overall survival.