CELL INTELLIGENCE · 肿瘤细胞治疗研究

Chimeric antigen receptor T cells (CAR-T cells) have been widely applied in hematologic malignancies. It has shown limited efficacy in the treatment of myeloid neoplasms. We retrospectively analyzed the safety and efficacy of CD123 CAR-T cells in 15 patients with myeloid neoplasms (ChiCTR2000041054). We investigated the effects of Venetoclax (Ven) on the proliferation, subset distribution, and cytotoxic activity of CD123 CAR-T cells, and explored the underlying mechanisms through multi-omics sequencing. Clinical trials indicated that the efficacy was poor. 4 patients achieved MRD-CR and 1 patient attained MRD + CR. Ven at 10nM significantly reduced the viability of HL-60, Molm13, and THP1 cells, but had no significant effect on CAR-T cells. Within a certain concentration range, as the concentration of Ven increased, the cytotoxic effect of CAR-T cells gradually intensified. In the group of 100 nM, the killing rate (p < 0.000) and cytokine secretion (p < 0.000, 0.001, and 0.028) were significantly higher than those in the group of 0nM. Further research demonstrated that pretreatment of CAR-T cells with Ven (to generate V-CD123 CAR-T cells) significantly enhanced their cytotoxic activity at a low effector-to-target ratios (1:10). Multi-omics analysis combining transcriptomic and metabolomic sequencing identified distinct alterations in key metabolic pathways between CD123 CAR-T cells and V-CD123 CAR-T cells. We propose that low-dose venetoclax combined with CD123 CAR-T cells enhances cytotoxicity, which may be attributed to metabolic optimization in CAR-T cells.