Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1–dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1–mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.