Depletion of CD8+ CAR T-cells leads to superior anti-tumor efficacy of pure CD4+ CAR T-cells against Acute Leukemias

Chimeric antigen receptor T-cell (CART) therapy has shown impressive therapeutic efficacy in several hematologic malignancies, however primary or secondary treatment failure remains a significant challenge driving translational research to improve the functionality of CARTs. Here, we show the optimal composition of CARTs targeting acute leukemias with respect to the content of CD4 ⁺ and CD8 ⁺ T-cells. Our analysis demonstrated that pure CD4 ⁺ CARTs exhibited superior antitumor activity and proliferative capacity in vitro and in vivo compared to CD8 ⁺ -containing CART products. Furthermore, the secretome of pure CD4 ⁺ CARTs, enriched for Th1 and Th2 cytokines, was more potent in stimulating the anti-leukemic activity of CARTs. Mechanistically, we found that the interaction with CD8 ⁺ CARTs induces apoptosis in CD4 ⁺ CARTs leading to their impaired functionality. Our findings demonstrate the superior efficacy and persistence of pure CD4 ⁺ CARTs against acute leukemias warranting further exploration of their therapeutic potential within early phase clinical trials.