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.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
靶向 CLDN18.2 的 STAR-T 细胞治疗胰腺癌：相比 CLDN18.2 CAR-T 最小化胃部脱靶毒性的策略
英文原题：CLDN18.2-targeting STAR-T cell therapy for pancreatic cancer: a strategy to minimize gastric off-tumor toxicity compared to CLDN18.2 CAR-T.
查看英文原题
CLDN18.2-targeting STAR-T cell therapy for pancreatic cancer: a strategy to minimize gastric off-tumor toxicity compared to CLDN18.2 CAR-T.
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中文摘要
Claudin18异构体2（CLDN18.2）主要在胃组织中表达，在胰腺癌（PC）中表达上调，是CAR-T（CAR-T）细胞疗法等创新治疗的关键靶点。然而，CLDN18.2在正常胃黏膜中也表达，因此CAR-T 疗效伴有显著的靶向但非肿瘤组织毒性（OTOT）风险。为解决这一问题，研究者开发了CLDN18.2特异性合成T细胞受体和抗原受体T（STAR-T）细胞。研究显示，STAR-T与CAR-T 细胞体外细胞毒性相近，但STAR-T体内胃损伤更少，尽管其抗肿瘤作用弱于CAR-T。胃镜临床检测证实STAR-T疗法胃部安全性良好，并可有效控制疾病。此外，在STAR-T细胞中加入IL-12 p40亚基，可在体外和动物实验中增强其功能。这些证据提示，CLDN18.2 STAR-T细胞可能是PC患者较CAR-T 更安全的替代方案，值得进一步开展临床试验。
展开英文摘要原文
Claudin18 isoform 2 (CLDN18. 2), primarily expressed in gastric tissue and upregulated in pancreatic cancer (PC), is a key target for innovative treatments like chimeric antigen receptor T (CAR-T) cell therapy.
However, CAR-T's effectiveness comes with a significant risk of on-target, off-tumor (OTOT) toxicity due to CLDN18. 2's presence in normal gastric mucosa. To address this, we developed CLDN18. 2-specific synthetic T cell receptor and antigen receptor T (STAR-T) cells.
Our research shows that STAR-T and CAR-T cells have comparable in vitro cytotoxicity, but STAR-T cells cause less gastric damage in vivo despite having weaker antitumor effects than CAR-T cells. Clinical tests with gastroscopes confirmed the gastric safety of STAR-T cell therapy, which effectively controlled the disease.
Additionally, incorporating the IL12 p40 subunit into STAR-T cells enhanced their function in both lab and animal studies. This evidence suggests that CLDN18. 2 STAR-T cell could be a safer alternative to CAR-T cell therapy for PC, meriting further clinical trials.
论文信息
- 作者
- Zhang W、Zeng M、Ma X、Chen J、Qiao J、He Z、Zhong G、Li Y
- 第一作者单位
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, China.China
- 通讯作者单位
- Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, China. yuli@szu.edu.cn.China
- 期刊
- Oncogene2025 Jul
- 原文标识
- PubMed 40301544 · DOI 10.1038/s41388-025-03414-z