肿瘤细胞治疗研究
英文原题：Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.
供者来源的 CD19-CAR-T 细胞为异基因造血干细胞移植后复发的 B 细胞恶性肿瘤提供了一种治疗选择，但常受限于植入不良、扩增不佳和持续性差。
供者来源的 CD19 CAR-T 细胞为异基因造血干细胞移植后复发的 B 细胞恶性肿瘤提供了一种治疗选择，但其植入、扩增和持续存在往往不理想。在一项首次人体研究（NCT01087294）中，我们发现，CAR 修饰的干细胞记忆 T（TSCM）细胞较常规 CAR-T 细胞扩增更多、持续时间更长；即使在较低剂量且未进行淋巴清除的情况下，也可实现完全缓解。CAR-TSCM 细胞仅引起轻度细胞因子释放综合征，主要涉及 IFN-γ。两种产品均可分化为效应细胞，但只有 CAR-TSCM 细胞能随时间稳健重建干细胞样细胞群。CAR-TSCM 细胞通过克隆更替得以持续存在；而持续存在的常规 CAR-T 细胞则源于早期扩增克隆的维持或收缩。常规 CAR-T 细胞的活性受扩增不足限制，而 CAR-TSCM 细胞治疗后的耐药主要由肿瘤及宿主相关因素驱动。这些发现表明，CAR-TSCM 细胞是具有前景的新一代 CAR-T 细胞治疗平台。
Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (T SCM ) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR T SCM cells induced mild cytokine-release syndrome, dominated by IFN- . Both products differentiated into effectors; however, only CAR T SCM cells robustly reconstituted the stem-like compartment over time. CAR T SCM cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR T SCM cells was driven primarily by tumor- and host-related factors. These findings establish CAR T SCM cells as a promising platform for next-generation CAR T cell therapies.
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