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在初级T细胞中,具有多重基因编辑的仿真抗原受体的非病毒表达
Dan Cappabianca1, Jingling Li2, Yueting Zheng2
1Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States.
Frontiers in bioengineering and biotechnology
|June 17, 2024
概括
这项研究表明,CRISPR/Cas9基因编辑可以通过敲除三个基因并添加一个CAR,有效地创建向癌症的CAR T细胞. 这种方法对于制造强效的全原细胞疗法是安全有效的.
科学领域:
- 细胞免疫疗法细胞免疫疗法
- 癌症基因组学 癌症基因组学
- 基因编辑技术 基因编辑技术
背景情况:
- 收养细胞疗法需要有效地设计具有瘤向受体的T细胞,如CAR或TCR.
- 通过CRISPR/Cas9基因组编辑,可以通过基因淘汰和合成受体插入来改变T细胞的功能.
- 多复合基因编辑,特别是非病毒传递,是T细胞疗法发展的重大挑战.
研究的目的:
- 为了证明高效的多重基因编辑和非病毒性CAR输送在人类T细胞中.
- 评估多重基因编辑在癌症免疫治疗中的安全性和有效性.
- 为了产生具有增强抗癌活性的GD2-CAR T细胞.
主要方法:
- 利用CRISPR/Cas9对人类T细胞中的B2M,TRAC和PD1基因进行多重淘汰.
- 采用非病毒传染来引入一种disialoganglioside GD2特异的化学抗原受体 (CAR).
- 评估基因编辑效率,非目标效应,染色体变异,T细胞表型和细胞毒性.
主要成果:
- 通过最小的非目标编辑和染色体异常,实现了B2M,TRAC和PD1的高效多重淘汰.
- 通过非病毒传递成功生成了缺乏B2M,TRAC和PD1表达的GD2-CAR T细胞.
- 工程GD2-CAR T细胞对GD2-表达神经母细胞瘤细胞的高细胞毒性已被证明.
- 在得到的CAR T细胞产品中证实了中央记忆细胞表型.
结论:
- 使用CRISPR/Cas9进行多重复合基因编辑,非病毒传递是一种可行且安全的T细胞治疗方法.
- 这种方法有助于快速高效地制造强效的全基性CAR T细胞产品.
- 开发的战略具有促进癌症免疫疗法发展的巨大潜力.
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