Inhibitory CARs Impede CAR-NK Cell Trogocytosis–Induced Tumor Escape

Trogocytosis, the receptor antigen ligation–induced transfer of cell-surface proteins between cells, has been observed in T cells and natural killer (NK) cells, with preclinical studies also demonstrating the occurrence of this process between chimeric antigen receptor (CAR) T cells and tumor cells, where it leads to antigen reduction and tumor relapse. Li and colleagues sought to determine if trogocytosis can also alter the efficacy of CAR-NK cell therapy and showed CAR activation promotes trogocytosis leading to reduced antigen density on tumor cells as well as loss of tumor control by CAR-NK cell therapy. Evaluation of the effects of trogocytosis on the effector functions of CD19-targeting CAR-NK cells revealed their initial increased activity, but this was accompanied by an increased susceptibility to fratricide and lack of a sustained antitumor response. Additional studies revealed that those CAR-NK cells that did not succumb to fratricide and underwent continuous antigen exposure acquired an exhausted phenotype due to antigen-induced self-engagement. Moreover, trogocytic antigen (TROG-antigen) expression reduced the persistence of CAR-NK cells, which was attributable to fratricide and led to development of a functional model following TROG-antigen acquisition on CAR-NK cells that involves activation first, followed by fratricide, functional exhaustion, and eventually tumor control failure. Clinically, a higher probability of relapse was observed in patients with highly expressing TROG-antigen CAR-NK cells, which supports that reduced antitumor efficacy is induced by CAR-mediated trogocytosis. Furthermore, use of a dual CAR system that includes an NK self-recognizing inhibitory CAR along with an activating CAR against a tumor antigen (AI-CAR system) reduced the occurrence of fratricide and improved the antitumor activity of the CAR-NK cells in in vivo models of both liquid and solid tumors. In summary, this study shows a mechanism of tumor escape after CAR-NK cell therapy through trogocytosis and suggests that use of the AI-CAR system can improve persistence of these cells as well as their antitumor activity, indicating its useful application moving forward.

Li Y, Basar R, Wang G, Liu E, Moyes JS, Li L, et al. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med 2022;28:2133–44.

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