UC San Diego

Chimeric Antigen Receptor (CAR) engineered NK cells have been shown to enhance the activities of NK cells against cancer in both preclinical and clinical studies. However, its efficacy against solid tumors is still limited due to the immunosuppressive tumor microenvironment. Here, we designed a novel CAR (named 2B4z-CAR) construct utilizing the intrinsic NKG2D receptors with the intracellular fusion of 2B4 and CD3ζ signaling domains, aiming to develop new CAR-NK-based therapeutics against solid tumors. In vitro, our novel CAR (2B4z-CAR) engineered NK92 cells showed potent antitumor activities against NKG2D ligand-expressing tumor cell lines while maintaining minimal off-target effects and toxicities. Notably, despite differences in surface expression, 2B4z-CAR-NK92 cells exhibited similar in vitro antitumor activities compared to that of a third-generation CAR-NK92 bearing CD28, 4-1BB, and CD3ζ signals. Collectively, we showed that the 2B4z-CAR could be a potential novel construct for CAR-NK-based immunotherapy against solid tumors expressing NKG2D ligands.