Superior Anti-tumor Efficacy of CD4+ CAR-T Cells against Acute Leukemias

ABSTRACT: While chimeric antigen receptor T-cell (CART) therapy has shown impressive therapeutic efficacy in several hematologic malignancies, primary or secondary treatment failure remains a significant challenge driving investigators to explore opportunities to improve the functionality of CART products. In this context, we aimed to explore the optimal compostion of CARTs targeting acute leukemias with respect to the content of CD4+ and CD8+ T-cells. Our analysis demonstrated superior antitumor activity and proliferative capacity both in vitro and in vivo for pure CD4+ CARTs compared to products containing CD8+ CARTs. Despite the enhanced proliferation, our murine xenograft models did not suggest an increased risk of toxicity associated with pure CD4+ CART products. Mechanistically, the secretome of CD4+ CARTs, that contained higher levels of Th1 and Th2 cytokines, was more potent in stimulating the anti-leukemic activity of CARTs. Furthermore, the presence of CD4+ CARTs induced stronger proliferation of CD8+ CARTs leading to a decreasing CD4/CD8 ratio within in the products over time. However, we found that the physical interaction between CD4+ and CD8+ CARTs impaired the functionality of CD4+ CARTs through induction of apoptosis. Taken together, the results of our study highlight the potential of pure CD4+ CARTs to enhance the efficacy and persistence of CART products against hematologic malignancies and warrant further testing within early phase clinical trials.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Blood

DISEASE(S): Acute Leukemia

SUBMITTER: Lianghao Mao  

LAB HEAD: Dr Ashok kumar Jayavelu

PROVIDER: PXD060508 | Pride | 2026-09-28

REPOSITORIES: Pride