Enhanced Safety and Antitumor Efficacy of Switchable Dual Chimeric Antigen Receptor-Engineered T Cells against Solid Tumors through a Synthetic Bifunctional PD-L1-Blocking Peptide.

Abstract

Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) therapy has an excellent efficacy in cancer treatment, especially its impressive results in hematological malignancies. Unfortunately, its application on solid tumors is challenged by the off-target effects caused by lacking of tumor specific antigens and the immunosuppression caused by the tumor microenvironment. We constructed a switchable dual receptor CAR-T cell (sdCAR-T) whose activity relied upon double antigens (mesothelin and fluorescein isothiocyanate) and was strictly controlled by a "switch" (FPBM) consisting of a PD-L1 blocking peptide conjugated to fluorescein isothiocyanate. SdCAR-T cells were activated only when FPBM and cognate tumor cells expressing both PD-L1 and mesothelin coexist. Importantly, long-term proliferation experiments in vitro and the pharmacodynamic study in vivo showed a stronger antitumor activity of this system compared to the second generation mesothelin CAR-T cells. In view of this novel treatment paradigm being safer and more effective than traditional CAR-T cells, it may become a new strategy for the treatment of solid tumors.