Th1/Th17轴调节了仿制抗原受体 (CAR) 的T细胞治疗毒性
bioRxiv : the preprint server for biology
|March 17, 2025
概括
通过阻断干扰素- (IFNγ) 可以减少CAR-T治疗的副作用,包括细胞因子释放综合征 (CRS) 和中性质衰竭. 这种方法可以减轻毒性,而不会损害CAR-T细胞的疗效,提供了潜在的新治疗策略.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 血液学 血液学 血液学
背景情况:
- 化学抗原受体 (CAR) -T疗法提高了患者的生存率,但可能导致严重的毒性,如细胞因子释放综合征 (CRS) 和免疫细胞相关的血液毒性 (ICAHT).
- 了解这些毒性背后的机制对于制定有效的管理策略至关重要.
研究的目的:
- 调查ICAHT的生物基础,特别是CAR-T治疗后CRS和中性衰竭的同时发生.
- 评估阻断干扰素- (IFNγ) 在缓解这些毒性的治疗潜力.
主要方法:
- 利用IL-2Rα淘汰赛小鼠模拟细胞因子毒性,诱导IL6,IFNγ和TNFα水平升高.
- 分析了骨髓中性粒细胞平衡,周围血液细胞计数和细胞因子概况,无论是在非瘤携带和Eμ-ALL瘤携带的小鼠中.
- 评估IFNγ阻断对CRS,中性质衰竭和CAR-T细胞疗效的影响.
主要成果:
- 在小鼠中进行的CAR-T疗法建模显示,促炎性细胞因子和M1-类巨细胞的升高,导致CRS和中性衰竭.
- 中性症与骨髓中性粒细胞平衡的破坏,亡的增加以及增殖/成熟的减少有关.
- IFNγ 阻塞成功地缓解了CRS和中性衰竭,而不会影响CAR-T的疗效.
- Th1-Th17不平衡,以增加IFNγ/IL-17A比率为特征,被确定为CRS和中性衰竭的驱动因素,降低IL-17A和G-CSF水平.
结论:
- 由IFNγ驱动的Th1-Th17不平衡与CRS和中性衰竭的同时发生有机械联系.
- 在患者中,外周血液中IFNγ/IL-17A比率的增加与高度CRS和中性质减退相关.
- 阻断IFNγ是一种有前途的策略,可以减少CAR-T疗法相关的CRS和中性质衰竭等毒性.
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