肿瘤细胞治疗研究
英文原题：Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion.
我们评估了11例接受单一批次cemacabtagene ansegedleucel（cema-cel）治疗的大B细胞淋巴瘤患者，cemacabtagene ansegedleucel是一种异体抗CD19 CAR T产品。
异体CAR T细胞可克服自体疗法的局限性，但受限于免疫排斥。我们评估了11例接受单一批次cemacabtagene ansegedleucel（cema-cel，一种异体抗CD19 CAR T产品）治疗的大B细胞淋巴瘤患者。尽管接受了相同的输注产品，患者仍表现出异质性的cema-cel扩增和临床结局。我们采用纵向TCRβ测序、单细胞分子谱分析和混合淋巴细胞反应试验进行的整合分析显示，在非扩增者中，预先存在的、受者来源的同种反应性CD8+ T细胞高频出现，介导了快速的CAR T排斥。此外，效应样特征而非干/中央记忆程序驱动了扩增者中一致的强克隆性CAR T扩增。
Allogeneic CAR T cells could overcome limitations of autologous therapies but are limited by immune rejection. We evaluated 11 patients with large B‑cell lymphoma treated with a single lot of cemacabtagene ansegedleucel (cema-cel), an allogeneic anti‑CD19 CAR T product. Despite receiving identical infusion products, patients exhibited heterogeneous cema-cel expansion and clinical outcomes. Our integrated analyses using longitudinal TCRβ sequencing, single‑cell molecular profiling, and mixed lymphocyte reaction assays revealed that high frequencies of pre‑existing, recipient-derived alloreactive CD8+ T cells mediated rapid CAR T rejection in non-expanders. Furthermore, effector-like features, rather than stem/central memory programs, drove robust clonal CAR T expansion consistently across expanders. We confirmed similar expansion patterns in two independent cohorts treated with a separate lot of cema-cel or an allogeneic anti-BCMA CAR T product. These findings highlight distinct cell‑extrinsic and cell‑intrinsic mechanisms that influence allogeneic CAR T performance and provide insights to optimize donor selection, manufacturing, and product design.
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