双功能囊基因工程 CAR-T 细胞使醇介导向能够克服 B 细胞淋巴瘤中的抗原逃逸
Jost Lühle1,2, Simon Krost3,4,5, Felix Goerdeler1,2
1Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, 14476 Potsdam, Germany.
ACS central science
|October 27, 2025
概括
新的氨酸工程CAR T细胞 (CysCAR-T) 准癌症的氧化还原失衡,克服B细胞淋巴瘤中的抗原损失. 这种方法显示出对持久缓解和减少各种癌症复发的希望.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 生物化学 生物化学
背景情况:
- 化学抗原受体 (CAR) T细胞治疗对血液癌症有效,但受到抗原阴性复发的限制.
- 瘤细胞通过降低目标抗原的调节来逃避CAR-T细胞,阻碍持久的缓解.
- 在B细胞淋巴瘤中观察到细胞外的氧化还原失衡,其特征是改变醇/二硫化物比率.
研究的目的:
- 开发用于癌症治疗的新型CAR T细胞,针对细胞外的氧化还原状态.
- 评估氨酸工程CAR T细胞 (CysCAR-T) 对B细胞淋巴瘤 (BCL) 的疗效.
- 评估双功能CAR T细胞结合CD19和氧化还原向的潜力.
主要方法:
- 工程设计的CysCAR-T细胞与氨酸修饰的抗体片段以准氧化还原失衡.
- 在体外对各种BCL亚型进行CysCAR-T细胞细胞毒性评估,包括抗原逃逸模型.
- 开发了双功能CD19-CysCAR-T细胞,同时向CD19和氧化还原状态.
- 在BCL小鼠模型中评估CD19-CysCAR-T细胞的体内疗效和毒性.
主要成果:
- 在实验室中,CysCAR-T细胞表现出对BCL亚型的强大和特异性细胞毒性,即使是在抗原逃逸场景中.
- 双功能CD19-CysCAR-T细胞有效地向CD19和改变的氧化还原状态,可能减轻抗原逃逸.
- 在体内研究表明,CD19-CysCAR-T细胞抑制了BCL携带小鼠的瘤生长和延长生存时间,没有系统性毒性.
结论:
- CysCAR-T细胞提供了一种新的策略,通过细胞外的氧化还原失衡来向癌细胞.
- 将CD19和氧化还原向与双功能CAR T细胞结合起来,可以克服抗原逃逸并减少BCL复发.
- 这种方法有可能提高CAR T细胞治疗在BCL和其他具有异常氧化还原状态的恶性瘤中的疗效.
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