Yuti P, Wutti-in Y, Sawasdee N, et al. Anti-CD19 Chimeric Antigen Receptor T Cells Secreting Anti-PD-L1 Single-Chain Variable Fragment Attenuate PD-L1 Mediated T Cell Inhibition. International Immunopharmacology. 2022; 113 (doi: 10.1016/j.intimp.2022.109442).
Researchers believe the efficacy of adoptive chimeric antigen receptor (CAR) T cell therapy can be made better by targeting T cell inhibition promoted by programmed death-ligand 1 (PD-L1). The protein is overexpressed in B cell malignancies, where T cell anti-tumor behavior may be hindered by the IFN-gamma cytokine. With earlier work suggesting that tumor-specific CAR-T cells secreting anti PD-L1 single-chain variable fragment (scFv) have promise for countering PD-L1-associated T cell inhibition and improving therapeutic efficacy, the current research worked with anti-CD19-CAR4 T cells equipped with this function. The findings indicate the engineered cells — referred to as anti-CD19-CAR5-T cells — generate more effective cytotoxicity than anti-CD19-CAR4-T cells, and do so in lower numbers. Secreted anti-PD-L1 promotes self-proliferation of the cells, and it also was found to restore the cytotoxic effect of anti-CD19-CAR4-T cells that was impaired by PD-L1 expression on the target tumor cells. Additionally, investigators report, anti-CD19-CAR5-T cells appear to release less IL-6, the proinflammatory properties of which lend themselves to cytokine-mediated toxicity. "This study demonstrated that PD-L1 blockade mediated by anti-PD-L1 scFv secreted from anti-CD19-CAR5-T cells can improve CAR-T antitumor efficiency prominently against PD-L1-positive tumors," the researchers conclude.