CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.

Abstract

Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.