模拟和解决克劳丁18.2向免疫疗法的点/瘤外毒性
Elizabeth J Carstens1,2, Kazuki Takahashi1,2,3, Naoya Sakamoto4,5
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nature communications
|November 2, 2025
概括
研究人员探索了Claudin 18.2 (CLDN18.2) 针对上部胃肠道癌症的向免疫疗法. 他们发现,降低CAR T细胞亲和力可以降低点/瘤外毒性,可能扩大治疗窗口.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 胃肠病学 胃肠病学
背景情况:
- 将免疫疗法扩展到固体瘤面临诸如"抗原困境"这样的挑战,目标抗原也存在于正常组织上.
- 克劳丁18.2 (CLDN18.2) 是上部胃肠道癌症的关键标,Zolbetuximab和CAR T细胞等疗法显示出有前途,但导致胃肠道毒性.
研究的目的:
- 研究针对CLDN18.2的免疫疗法的机制及其相关的毒性.
- 开发新的CLDN18.2-向CAR T细胞,改善治疗窗口.
主要方法:
- 对Zolbetuximab相关的胃侵蚀的临床病例的分析.
- 使用CLDN18.2-向CAR T细胞治疗的小鼠模型对点/瘤外毒性的临床前表征.
- 开发和测试具有不同亲属性的全人类VH单域CAR.
主要成果:
- 临床数据证实了与zolbetuximab治疗相关的胃侵蚀性病变.
- 临床前模型证明了针对CLDN18.2-向CAR T细胞的上/外胃毒性.
- 较低亲和度的CLDN18.2 CAR T细胞显示毒性降低,同时保持抗瘤功效.
结论:
- 在CLDN18.2向治疗中,点/瘤外毒性是一个重大问题.
- 卡尔-T细胞亲和力是平衡疗效和毒性的关键因素.
- 开发较低亲和度的CLDN18.2CAR可能为上部肠道癌症提供更安全的治疗策略.
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