线粒体解偶联剂 BAM15 增强 CD7CAR-T(CD7-) 细胞功能并减少细胞因子释放以治疗 T 细胞恶性肿瘤

Traditional therapies for relapsed/refractory T-cell malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphomas, have limited efficacy. Chimeric antigen receptor T-cell (CAR-T) therapy has shown potential in treating hematologic malignancies, but challenges such as tumor immune evasion, CAR-T resistance, and cytokine release syndrome (CRS) hinder its clinical application. In this study, we generated CD7CAR-T CD7- cells by modifying naturally occurring CD7 negative T cells from human peripheral blood with a novel CD7 targeted CAR construct.

The cytotoxic efficacy of CD7CAR-T CD7- cells against CD7 positive T cell malignancies was assessed through in vitro experiments and xenograft mouse models. To address CAR-T therapy limitations, we identified BAM15, a mitochondrial uncoupling agent, from a small molecule library. BAM15 enhanced the cytotoxic function of CD7CAR-T CD7- cells in a concentration-dependent manner while reducing cytokine release profile in both cellular assays and xenograft models.

Notably, at low concentrations (2. 5 M, 1 M and 0. 5 M), BAM15 improved antitumor efficacy at suboptimal effector-to-target ratios (E:T = 1:1 and 1:2), reduced inflammatory cytokines like IL-6 and TNF , and alleviated inflammatory cell infiltration in lung and liver.

This study confirms the feasibility of constructing CD7CAR-T CD7- cells from CD7 - T cells and first reveals the synergistic effects of BAM15 on CD7CAR-T CD7- cells, for overcoming dose limitations and CRS of CAR-T therapy, and providing a novel strategy for T-cell malignancies.