Enhancing the effectiveness of Chimeric Antigen Receptor (CAR) T cells against tumors through CRISPR/Cas9-mediated PD-1 disruption

Abstract

Immunotherapies involving chimeric antigen receptor (CAR) T cells and checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) antagonists, have shown promise in treating cancer. The combined benefits of these medicines are yet not fully understood. In this work, it was discovered that human CAR T cells become hypo-functional due to the expression of programmed cell death ligand 1 (PD-L1) on tumor cells, which reduces their efficacy in a sub-cutaneous xenograft model. To solve this problem, scientists created a procedure that combines lentiviral transduction with Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing to produce PD-1-deficient anti-CD19 CAR T cells. Disrupting the Pdcd1 (PD-1) gene led to increased killing of tumor cells in vitro and improved clearance of PDL1+ tumor xenograft in vivo. This study highlights the potential of precision genome engineering to enhance next-generation cell therapies and improve the efficacy of CAR T cell immunotherapy.