通过以为中心的CAR对细胞内瘤蛋白进行交叉HLA向
Mark Yarmarkovich1, Quinlen F Marshall1, John M Warrington1
1Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Nature
|November 4, 2021
概括
这项研究引入了以基为中心的仿制抗原受体 (CAR),以向细胞内神经母细胞瘤蛋白,克服了新抗原疗法的局限性,并扩大了特定人白细胞抗原 (HLA) 类型的患者的治疗选择.
科学领域:
- 免疫学
- 癌症学
- 生物技术
背景情况:
- 大多数癌症免疫疗法都针对由人类白细胞抗原 (HLA) 分子呈现的突变 (新抗原).
- 基因突变负担较低的癌症,如神经母细胞瘤,
- 神经母细胞瘤是由表观遗传失调而不是突变驱动的,这对当前的免疫疗法来说是一个挑战.
研究的目的:
- 开发一种针对细胞内瘤的新型免疫治疗策略.
- 设计能够识别特定瘤相关的基受体 (CAR).
- 在CAR T细胞治疗中克服人类白细胞抗原 (HLA) 的限制.
主要方法:
- 在HLA-A*24:02上提供来自PHOX2B的神经母细胞瘤特异性 (QYNPIRTTF) 的鉴定.
- 使用反策略开发以为中心的CAR.
- 用计算建模来预测与其他HLA类型的交叉反应性.
- 在体外和体内验证CAR T细胞对神经母细胞的疗效.
主要成果:
- 以为中心的CAR成功准了PHOX2B衍生的QYNPIRTTF.
- 通过HLA-A*23:01和HLA-B*14:02识别,CARs显示了交叉反应性.
- 在实验室中观察到表达这些HLA的神经母细胞的强效和特异性杀死.
- 在小鼠模型中实现了完整的瘤回归.
结论:
- 以为中心的CAR提供了一种有前途的方法来向以前无法获得免疫治疗的细胞内瘤蛋白.
- 这一策略通过克服传统的HLA限制,扩大了CAR T细胞治疗的适用性.
- 这些发现表明,在神经母细胞瘤和其他低突变负担的癌症中,患者可能获得更广泛的益处.
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