Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo

The efficacy of CAR-T cell therapy against poorly responding tumors has been enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to co-express factors that boost CAR-T cell function in the tumor microenvironment. Here we modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells work in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1(+) hematologic and solid tumors. Efficacy was similar or better to that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach could improve safety as the secreted scFv remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.