CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
外周血中性粒细胞参与晚期胃癌 Claudin18.2 特异性 CAR-T 细胞治疗耐药
英文原题：Peripheral blood neutrophils contribute to Claudin18.2-specific CAR-T cell treatment resistance in advanced gastric cancer.
查看英文原题
Peripheral blood neutrophils contribute to Claudin18.2-specific CAR-T cell treatment resistance in advanced gastric cancer.
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研究概要
本研究强调 NLR 是接受 CLDN18.2 特异性 CAR-T 细胞治疗的晚期 GC 患者的重要预后因素，并为中性粒细胞介导的治疗耐药提供了见解。
中文摘要
背景
靶向Claudin18.2（CLDN18.2）的嵌合抗原受体（CAR）T细胞治疗为晚期胃癌（GC）带来希望，但疗效存在差异。本研究评估中性粒细胞与淋巴细胞比值（NLR）对CAR-T 治疗的预后价值，并阐明治疗耐药的分子机制。
方法
分析接受CLDN18.2特异性CAR-T 治疗的胃癌患者。评估客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）和总生存期（OS），采用Kaplan-Meier法、log-rank检验和Cox回归分析生存。通过外周血单细胞RNA测序研究促肿瘤循环中性粒细胞的机制。
结果
NLR升高与较低ORR（34.2%比55.9%，P<.001）、较短中位PFS（3.6比8.0个月，P<.001）和OS（5.6比13.8个月，P<.001）显著相关。单细胞测序鉴定出与疾病进展相关的循环中性粒细胞亚群NE-3。NE-3表达促肿瘤因子MMP-9，并富集IL-17信号通路。进展疾病（PD）组中性粒细胞与T细胞间的相互作用较部分缓解（PR）组更显著。
结论
本研究强调，NLR是接受CLDN18.2特异性CAR-T 治疗晚期胃癌患者的重要预后因素，并提供了中性粒细胞介导治疗耐药的机制线索。仍需进一步验证，并探索减轻中性粒细胞诱导免疫抑制的策略。试验注册号：NCT03874897。
展开英文摘要原文
BACKGROUND
Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR)-T cell treatment holds promise for advanced gastric cancer (GC) but has variable efficacy. This study investigates the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in CAR-T cell treatment and elucidates the molecular mechanisms of treatment resistance.
METHODS
GC patients treated with CLDN18.2-specific CAR-T cell treatment were analyzed. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival analyses utilized Kaplan-Meier methods, log-rank tests, and Cox regression. Single-cell RNA sequencing was performed on peripheral blood samples to investigate the mechanisms of pro-tumor circulating neutrophils.
RESULTS
Elevated NLR was significantly associated with lower ORR (34.2% vs. 55.9%, P < 0.001), shorter median PFS (3.6 vs. 8.0 months, P < 0.001), and OS (5.6 vs. 13.8 months, P < 0.001). Single-cell sequencing identified a circulating neutrophil subcluster (NE-3) linked to disease progression. NE-3 expressed pro-tumoral factors (MMP-9), and was enriched in the IL-17 signaling pathway. The cellular interactions between neutrophils and T cells were more prominent in progression disease (PD) group than in partial response (PR) group.
CONCLUSIONS
This study highlights NLR as a significant prognostic factor in advanced GC patients receiving CLDN18.2-specific CAR-T cell treatment and provides insights into neutrophil-mediated treatment resistance. Further validation and exploration of strategies to mitigate neutrophil-induced immunosuppression are needed. TRIAL REGISTRATION: NCT03874897.
论文信息
- 作者
- Li J、Tao M、Liu L、Liu C、Ma M、Liu D、Zhang P、Zhang M
- 第一作者单位
- Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China.China
- 通讯作者单位
- Beijing Key Laboratory of Cell & Gene Therapy for Solid Tumor, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Centre, Peking University Cancer Hospital & Institute, Beijing, China. changsongqi@bjmu.edu.cn.China
- 文献类型
- I 期临床试验 · 多中心研究
- 期刊
- British journal of cancer2025 Jun
- 原文标识
- PubMed 40246985 · DOI 10.1038/s41416-025-03015-3
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