决定异体CAR-T细胞排斥与扩增的细胞和分子机制
Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion
异体CAR-T细胞（取自健康供者、可批量生产）有望突破自体CAR-T的产能限制，但会被受者免疫系统排斥。研究分析了11例接受同一批次cemacabtagene ansegedleucel（一种靶向CD19的异体CAR-T产品）的大B细胞淋巴瘤患者，尽管输入产品完全相同，患者的细胞扩增和疗效差异很大。通过纵向T细胞受体测序、单细胞分子图谱和混合淋巴细胞反应，发现扩增差的患者体内预先存在大量受者来源的同种反应性CD8阳性T细胞，会迅速排斥CAR-T；而扩增好的患者，CAR-T细胞呈现效应样而非记忆样特征。结论提示可通过供者选择和产品设计优化异体CAR-T疗效。
为什么推荐给您：首次系统揭示异体CAR-T排斥与扩增的细胞机制，属重要新机制发现，可指导产品设计。
不需要生物学背景，多打比方
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摘要Abstract
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.