KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape

Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a 'don't kill me' signal to NK cells upon engagement with their TROG(+) siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity. A new dual-chimeric antigen receptor (CAR) system enhances the antitumor activity of CAR natural killer cells and makes them less susceptible to therapeutic resistance in preclinical models.

Automated summary

The activation of chimeric antigen receptor (CAR) in natural killer (NK) cells promotes the transfer of tumor-specific antigen from tumor cells to NK cells, resulting in decreased tumor antigen density and impaired CAR-NK cell targeting ability. This phenomenon can lead to self-recognition and continuous CAR-mediated engagement, causing cell death in NK cells expressing the trogocytic antigen (NKTROG+) and reduced NK cell responsiveness. However, a dual-CAR system that incorporates both an activating CAR against the tumor antigen and an inhibitory NK self-recognizing CAR can prevent trogocytic antigen-mediated cell death in NK cells, while maintaining activation signaling against the tumor antigen, thereby enhancing CAR-NK cell activity.