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HLA-A2 CAR/IL-2-CISC工程Treg显示强大的in vitro和in vivo抗原特异性调节功能

Subhash K Tripathi¹, Annaiz Grimm¹, Noelle P Dahl¹

¹Center for Immunity and Immunotherapies and the Program for Cell and Gene Therapy, Seattle Children's Research Institute, 1920 Terry Avenue, Seattle, WA 98101, USA.

Molecular therapy. Methods & clinical development

|September 16, 2025

概括

具有仿真抗原受体 (CAR-Treg) 的工程T调节细胞 (Treg) 显示出治疗自身免疫性疾病和移植排斥的前景. 这项研究使用基因编辑生成了抗原特异性CAR-Treg,在临床前模型中证明了它们的有效性.

科学领域:

免疫学免疫学免疫学
细胞疗法细胞疗法
基因编辑基因编辑

背景情况:

化学抗原受体表达T调节细胞 (CAR-Treg) 是一种有前途的细胞疗法,用于自身免疫性疾病和移植排斥.
之前的研究使用了天然Treg,但这项研究重点是工程Treg (EngTreg).

研究的目的:

使用同质导向修复 (HDR) 基因编辑生成抗原特异性CAR-Treg.
在临床前模型中评估这些工程Treg的治疗疗效.

主要方法:

利用HDR基因编辑创建EngTreg共同表达FOXP3和化学诱导IL-2信号复合体 (CISC).
通过lentiviral转导或双HDR编辑实现了CAR表达,针对TRAC位置.
在试验室中评估了EngTreg免疫表型,细胞因子分泌和细胞毒性.
在异源移植与宿主疾病 (GvHD) 模型中评估了A2CAR EngTreg的疗效.

主要成果:

生成的A2CAR+ CISC+ EngTreg具有Treg免疫表型,低的促炎细胞因子分泌和低的细胞毒性.
与多克隆EngTreg相比,A2CAR EngTreg在异源GvHD模型中显示出更高的治疗效果.
在体内激活IL-2 CISC增强了A2CAR EngTreg的疗效.

结论:

使用CAR向实现抗原特异性EngTreg的有效生成是可行的.
A2CAR EngTreg显示了对移植和自身免疫性疾病的治疗潜力.

关键词:

这是一款A2CAR.这就是CRISPR/Cas9的作用.这是EngTregreg.这是一个GvHD.这就是IL-2-CISC.对抗原特异性抑制抑制.双HDR编辑编辑双HDR编辑工程师Treg设计的移植与宿主疾病的对比.

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