Targeting PD-L1 in non-small cell lung cancer using CAR T cells

Abstract

Abstract Antibodies against programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the landscape of therapies for non-small cell lung carcinoma (NSCLC); however, the majority of patients do not respond to these agents. In addition, hyperprogressive disease (HPD) develops in a larger portion of NSCLC patients treated with PD-1/PD-L1 inhibitors than in patients treated with standard chemotherapy. The use of chimeric antigen receptor (CAR) T cells has been successful to treat blood cancers but not for solid tumors like NSCLC. In this work, we constructed CAR T cells that target PD-L1 and evaluated their efficacy in NSCLC with either high or low PD-L1 expression. PD-L1-CAR T cells exhibited antigen-specific activation, cytokine production, and cytotoxic activity against PD-L1 high NSCLC cells and xenograft tumors. Furthermore, the addition of a subtherapeutic dose of local radiotherapy improved the efficacy of PD-L1-CAR T cells against PD-L1 low NSCLC cells and tumors. Our findings indicate that PD-L1-CAR T cells represent a novel therapeutic strategy for patients with PD-L1-positive NSCLC, particularly for those who are susceptible to HPD.