PO.TB10.04 · 肿瘤生物学
免疫系统状态塑造套细胞淋巴瘤对CAR-T治疗的临床反应
Immune system state shapes clinical response to CAR-T therapy in mantle cell lymphoma
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摘要 Abstract
中文摘要
背景：
CAR-T治疗已彻底改变了复发/难治性套细胞淋巴瘤（MCL）的治疗，但仍有相当一部分患者复发或治疗无效。驱动复发和难治的生物学机制仍不明确，尤其是系统性免疫动态在塑造CAR-T疗效中的影响。
方法：
对44例接受brexucabtagene autoleucel治疗的MCL患者的56份血液样本进行了单细胞RNA测序（scRNA-seq），包括24例长期反应者（CAR-T前样本）、17例复发患者（其中13例具有配对的CAR-T前和复发后样本）以及3例难治患者（配对的CAR-T前和后样本）。开展整合计算分析，以单细胞分辨率定义免疫系统状态（ISS）并将其与临床结局相关联。一个AI辅助的预测模型正在开发中以用于临床应用。
结果：
对总计156,852个细胞的scRNA-seq分析揭示了三大类与临床结局密切相关的ISS：基于细胞毒性和免疫抑制特征分为免疫监视（低风险）、免疫平衡（中风险）和免疫抑制（高风险）。低风险患者表现出强劲的细胞毒活性和持久缓解，而复发则涉及向高风险状态的演变，其特征为T细胞和NK细胞耗竭以及单核细胞富集。所有难治患者在CAR-T治疗前均表现为高风险ISS。复发后或难治病例中，T细胞亚群（CTL、Tex、TCM）和NK细胞的耗竭评分和检查点表达（如TIGIT、LAG3）升高。这些发现确立了ISS作为MCL中CAR-T反应和复发风险的预测框架。
结论：
ISS通过捕捉系统性免疫动态，为预测MCL中的CAR-T反应提供了一个具有临床可操作性的框架。ISS指导的风险分层可为MCL中的CAR-T优化和合理联合策略提供信息。
查看英文原文 English abstract
Background:
CAR-T therapy has transformed treatment for relapsed/refractory mantle cell lymphoma (MCL), yet a significant subset of patients relapses or fails to respond. The biological mechanisms driving relapse and refractoriness remain poorly defined, particularly the influence of systemic immune dynamics in shaping CAR-T efficacy.
Methods:
Single-cell RNA sequencing (scRNA-seq) was performed on 56 blood samples from 44 MCL patients treated with brexucabtagene autoleucel, including 24 long-term responders (pre-CAR-T samples), 17 relapsed patients (13 with paired pre-CAR-T and post-relapse samples), and 3 refractory patients (paired pre- and post-CAR-T samples). Integrative computational analysis was conducted to define immune system state (ISS) at single-cell resolution and correlate them with clinical outcomes. An AI-assisted predictive model is under development for clinical application.
Results:
scRNA-seq analysis of 156,852 cells in total revealed three major ISS categories strongly associated with clinical outcomes: immune surveillance (low-risk), immune equilibrium (intermediate-risk), and immune suppression (high-risk), based on cytotoxicity and immunosuppressive profiles. Low-risk patients exhibited robust cytotoxic activity and durable remission, whereas relapse involved evolution to high-risk states characterized by T-cell and NK-cell exhaustion and monocyte enrichment. All refractory patients displayed high-risk ISS prior to CAR-T. Exhaustion scores and checkpoint expression (e.g. TIGIT, LAG3) were elevated in T-cell subsets (CTL, Tex, TCM) and NK cells post-relapse or in refractory cases. These findings establish ISS as a predictive framework for CAR-T response and relapse risk in MCL.
Conclusions:
ISS provides a clinically actionable framework for predicting CAR-T response in MCL by capturing systemic immune dynamics. ISS-guided risk stratification may inform CAR-T optimization and rational combination strategies in MCL.
利益披露 Disclosure
V. Jiang, None..
Q. Cai, None..
H. Kim, None..
C. Yu, None..
Y. Li, None..
J. Vargas, None.
M. Wang,
Abbvie ).
AstraZeneca ).
Bantam Pharma ).
Genmab ).
Genentech ).
Innocare ).
Janssen ).
Juno Therapeutics ).
Kite Pharma ).
Eli Lilly ).
Nurix Therapeutics ).
Oncternal ).
Pharmacyclics ).