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使用基于NKG2D的适配器CAR T细胞进行固体瘤免疫疗法

Jana Obajdin¹, Daniel Larcombe-Young¹, Maya Glover²

¹King's College London, School of Cancer and Pharmaceutical Sciences, CAR Mechanics Lab, London SE1 9RT, UK.

Cell reports. Medicine

|November 20, 2024

概括

针对NKG2D配体 (NKG2DLs) 的工程T细胞显示出强大的抗瘤活性. 新的NKG2D/Dap10-12仿真抗原受体 (CAR) 疗法消除了瘤,并改善了模型中的生存率.

科学领域:

免疫学免疫学免疫学
癌症生物学癌症生物学
细胞疗法细胞疗法

背景情况:

NKG2D配体 (NKG2DLs) 在癌细胞上得到广泛表达,具有治疗点.
现有的仿真抗原受体 (CAR) 策略在向NKG2DL表达瘤方面存在局限性.

研究的目的:

开发和评估一种名为NKG2D/Dap10-12的新型适应器CAR,用于向癌细胞上的NKG2DL.
在临床前癌症模型中评估NKG2D/Dap10-12CAR T细胞的疗效和潜在机制.

主要方法:

工程T细胞与Dap10和Dap12内域 (NKG2D/Dap10-12 CAR) 组成的融合蛋白共同表达NKG2D.
在具有NKG2DL表达瘤的已建立异种移植模型中评估治疗疗效.
在一组CAR中进行结构功能分析,以确定效力的关键决定因素.
分析工程T细胞的细胞代谢和转录组学.

主要成果:

在多个异种移植模型中,NKG2D/Dap10-12 T 细胞显示出令人信服的疗效,根除或控制瘤.
实现了持久的反应,长期存活和拒绝瘤再挑战.
疗效明显超过了临床阶段NKG2D-CD3ζ CAR. 的疗效.
功效与信号单位的接近,NKG2D表达,适应器结构,外源Dap10和ITIM号码有关.

结论:

NKG2D/Dap10-12 CAR代表了针对NKG2DL表达性癌症的强有力的新策略.
优化的CAR设计,包括适配器结构和信号图案,对于治疗疗效至关重要.
NKG2D/Dap10-12 CAR T 细胞表现出增强的代谢适应性和重新编程的转录以改善抗瘤功能.

关键词:

在Dap10中使用Dap10 在Dap12中使用Dap12.在NKG2D中,它是NKG2D.适配器适配器适配器适配器仿制性抗原受体的仿制性抗原受体

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