与ATM-缺乏T细胞的逆转录病毒CAR转导相关的基因毒性
Meir Rozenbaum1, Reut Fluss2,3, Victoria Marcu-Malina4
1Cell Therapy Lab, Sheba Medical Center, Tel Hashomer, Israel.
Blood cancer discovery
|May 15, 2024
概括
过敏性脑膜炎 (ATM) 缺陷在制造过程中损害了仿真抗原受体 (CAR) T细胞基因组完整性,增加了染色体损伤风险. 这突出了ATM机的亮点.
科学领域:
- 免疫学 免疫学 免疫学
- 遗传学 遗传学 是一个
- 在瘤学瘤学.
背景情况:
- 像ATM这样的DNA损伤反应基因的体质变异在血液癌症中很常见.
- ATM蛋白对于修复双链DNA断裂至关重要.
- 生殖线ATM缺陷会导致 - 光学 (A-T),导致放射敏感性,免疫缺陷和淋巴细胞癌症风险.
研究的目的:
- 为了研究来自A-T (ATM-/-) 患者,异胞捐赠者 (ATM+/-) 和健康捐赠者所获得的嵌合抗原受体 (CAR) T细胞.
- 评估ATM缺陷在逆转录病毒转导过程中对CAR T细胞功能和基因组完整性的影响.
主要方法:
- 来自ATM-/- ,ATM+/-和健康捐赠者的初级T细胞被用于生成CAR T细胞.
- 使用逆转录病毒转导引入CAR到T细胞中.
- 使用下一代长读测序来分析CAR插入部位的染色体病变.
主要成果:
- 虽然ATM-/-T细胞可以被CAR转化并繁殖,但表现出一些功能障碍.
- 逆转录病毒转导CAR到ATM-/- T细胞导致插入部位的染色体病变率高.
- 基因组不稳定性在ATM缺乏T细胞的CAR插入部位被证实.
结论:
- 在逆转录病毒制造过程中,ATM对于保持CAR T细胞的基因组完整性至关重要.
- 由于ATM缺陷,在CAR T细胞中存在染色体转位和潜在的白血病发生的风险.
- 这项研究强调了基因改造细胞中基因组完整性控制的重要性,特别是在DNA修复缺陷的患者中.
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