易布鲁替尼和PD-1阻断在胰腺癌的临床前模型中增强了针对美索林的CAR-T细胞疗法
Alexander Armstrong1, Graziella van der Plancke2, Sae Nishiguchi3
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States.
概括
这项研究通过将CAR-T细胞与ibrutinib和PD-1阻断药物相结合,增强了针对瘤及其微环境的疗效,从而增强了对胰腺癌的仿真抗原受体 (CAR) T细胞疗法.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 生物技术是生物技术.
背景情况:
- 胰腺管道腺癌 (PDAC) 由于其免疫抑制微环境和密集的细胞外基质,对CAR T细胞疗法具有抗性.
- 与癌症相关的纤维细胞 (CAFs) 通过沉积细胞外基质,阻碍CAR-T细胞透,为这种屏障做出贡献.
研究的目的:
- 通过解决瘤中甲蛋白分泌和CAR-T细胞功能障碍等障碍,优化PDAC的CAR-T细胞疗法.
- 评估合理的药物组合和输送策略,以提高向美索林的CAR-T细胞的治疗疗效.
主要方法:
- 利用临床前PDAC模型测试向美索林的CAR-T细胞与增加美索林表达和支持T细胞功能的药物结合使用.
- 对比静脉输入与腹膜内输送途径,用于治疗腹膜转移.
主要成果:
- 易布鲁替尼在PDAC模型中增强了CAR-T细胞扩张,Th1倾斜和抗瘤活性.
- PD-1阻塞协同改善了CAR-T细胞的抗瘤功能,腹膜内输送在腹膜疾病中优越.
- 一种ADAM10/17抑制剂通过防止美索林脱落而改善了体外瘤杀伤,但没有提高体内疗效.
结论:
- 确定了临床可行的策略,以优化针对PDAC的CAR T细胞治疗.
- 计划进行一期临床试验,以测试 mesothelin-FAP CAR-TEAM T 细胞与或没有 ibrutinib 或 PD-1 阻塞.
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