CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells

• DOI: 10.4049/jimmunol.196.supp.214.24
• Publication Date: 2023-01-01T10:54:15Z
• Authors: Levi Rupp; Kathrin Schumann; Kole T Roybal; Alexander Marson; Wendell A Lim
• Keywords: Immune checkpoint; Cancer Immunotherapy; Cell therapy

Abstract Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize the programmed cell death protein 1 [PD-1] pathway) have both opened new avenues for cancer treatment, but clinical potential of combination blockade CAR therapy remains incompletely explored. Here we show ligand (PD-L1) expression on tumor can render human (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired clearance a sub-cutaneous mouse xenograft model. To overcome this suppressed anti-tumor response, developed protocol combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing lentiviral transduction to generate PD-1 deficient, anti-CD19 cells. disruption augmented mediated killing vitro enhanced PD-L1+ xenografts vivo. This study demonstrates improved therapeutic efficacy Cas9-edited highlights precision genome engineering enhance next-generation therapies uncover mechanisms regulating immune function.