Cao Guoshuai, Hu Yifei, Pan Tony, Tang Erting, Asby Nicholas, Althaus Thomas, Wan Jun, Riedell Peter A, Bishop Michael R, Kline Justin P, Huang Jun
Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, 60637, USA.
Pritzker School of Medicine, University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2025 May 6;16(1):4205. doi: 10.1038/s41467-025-59298-w.
Advancements in chimeric antigen receptor (CAR) T-cell therapy for treating diffuse large B-cell lymphoma (DLBCL) have been limited by an incomplete understanding of CAR T-cell differentiation in patients. Here, we show via single-cell, multi-modal, and longitudinal analyses, that CD8 CAR T cells from DLBCL patients successfully treated with axicabtagene ciloleucel undergo two distinct waves of clonal expansion in vivo. The first wave is dominated by an exhausted-like effector memory phenotype during peak expansion (day 8-14). The second wave is dominated by a terminal effector phenotype during the post-peak persistence period (day 21-28). Importantly, the two waves have distinct ontogeny from the infusion product and are biologically uncoupled. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. We demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes.
嵌合抗原受体（CAR）T细胞疗法在治疗弥漫性大B细胞淋巴瘤（DLBCL）方面的进展受到对患者体内CAR T细胞分化认识不足的限制。在此，我们通过单细胞、多模态和纵向分析表明，接受axi-cabtagene ciloleucel成功治疗的DLBCL患者的CD8 CAR T细胞在体内经历了两个不同的克隆扩增波。第一波在扩增高峰期（第8 - 14天）以耗竭样效应记忆表型为主。第二波在高峰期后持续期（第21 - 28天）以终末效应表型为主。重要的是，这两个波与输注产物具有不同的个体发生过程，并且在生物学上是不相关联的。第一波的前体细胞表现出更多效应样特征，而第二波的前体细胞表现出更多干细胞样特征。我们证明，CAR T细胞的扩增和持久性是由克隆、表型和个体发生上不同的CAR T细胞群体介导的，这些群体具有互补的临床作用。
