Abstract
CAR T cells reduce target antigen density on tumor cells and T cell activity via trogocytosis.
Major Finding: CAR T cells reduce target antigen density on tumor cells and T-cell activity via trogocytosis.
Concept: Trogocytosis contributes to antigen density reduction and T-cell malfunction.
Impact: Rational combinatorial targeting with adapted costimulation strategies may block antigen-low relapse.
Despite high overall complete response rates, relapse occurs in a significant fraction of patients with B-cell leukemia who have received chimeric antigen receptor (CAR) T-cell therapy. Although mechanisms of antigen-negative tumor escape have been previously reported, the origins of antigen-low relapse are less clear. Hamieh and colleagues modeled CAR T-cell therapy relapse by infusing the NALM6 acute lymphoblastic leukemia model with limiting doses of CD19-targeted CAR T cells harboring either CD28 or 4-1BB costimulatory domains (CAR 19-28ζ and CAR 19-BBζ, respectively) and characterized antigen (CD19) expression in the relapsed disease. In vivo and tumor cell–CAR co-culture assays revealed that, unlike in antigen-negative relapses where antigen loss is permanent, antigen loss on tumor cells was reversible and occurred via CAR-mediated trogocytosis, which resulted in the expression of CD19 on the CAR T cells. Furthermore, this phenomenon was observed in vitro with additional CAR T-cell antigens such as CD22 and BCMA, and a similar antigen escape profile was observed in vivo using CD22-targeted CAR T cells. Similarly, CAR T-cell therapy, particularly CAR 19-BBζ, was less efficacious in NALM6 cells exhibiting medium to low CD19 expression. In addition to promoting tumor escape, trogocytic antigen extraction also contributed to relapse by promoting T-cell exhaustion and fratricide T-cell killing in both 19-28ζ and 19-BBζ CAR T cells. In vitro single-cell cytotoxicity assays of 2 or 1 CAR T cell per tumor cell demonstrated that the frequency of tumor cell killing increased dramatically when a tumor cell was targeted by 2 CAR T cells rather than just 1, suggesting that higher CAR:tumor cell ratios could overcome trogocytosis-mediated tumor escape through cooperative killing. Taken together, these findings in multiple animal models support the design of target antigen density–adapted CAR strategies to prevent antigen-low tumor relapse.
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