Augmenting CAR NK cell Anti-tumor Activity by Synapse Tuning

Introductory Paragraph Chimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics 1-3 . Natural Killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. We sought to tune CAR synapses in NK cells by adding an intracellular scaffolding protein binding site to the CAR. We employed a PDZ binding motif (PDZbm) that specifically binds Scribble 4 resulting in additional scaffolding crosslinking to enhance synapse formation and cell polarization 5,6 . Combined effects of this novel CAR design resulted in increased effector cell functionality in vitro and in vivo . Synapse-tuned CAR-NK cells exhibited amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells, and prolonged survival with tumor clearance in two solid tumor models. Thus, synapse tuning has the potential to improve the efficacy of CAR-based cell therapeutics.