设计一种双特异性 γδ T 细胞受体,用于癌症免疫治疗
David M Davies1, Giuseppe Pugliese1,2, Ana C Parente Pereira3
1Leucid Bio Ltd., Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
Biology
|March 27, 2024
概括
针对癌症的工程T细胞显示双重特异性. 研究人员修改了一种玛三角T细胞受体 (TCR),以识别光原原和瘤特异性整合素,增强癌症免疫治疗潜力.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 分子工程分子工程分子工程
背景情况:
- 马三角形 (γδ) T 细胞弥合了先天性和适应性免疫力,提供了对癌症的免疫监测.
- 可以将Vγ9Vδ2 γδ T细胞受体 (TCR) 改造为T细胞,以向光抗原 (PAgs).
- 目前的癌症免疫疗法使用在临床研究中的γδ TCR工程T细胞.
研究的目的:
- 通过结合一种瘤结合质来增强G115 γδ TCR的癌症特异性.
- 研究双特异性T细胞对表达PAg和表达αvβ6的瘤细胞的疗效.
- 评估插入对T细胞激活和细胞因子释放的影响.
主要方法:
- 基因修饰G115 γδ TCR通过将由口疫病毒A20衍生出的12mer插入CDR3 δ2区域.
- 选择A20因其高亲和度与αvβ6整体素的结合,在各种固体瘤上表达.
- 对PAg呈现性和αvβ6表达性瘤细胞的T细胞中介细胞毒性的评估.
- 在T细胞激活时释放的干扰素 (IFN) -γ的测量.
主要成果:
- 与对照G115细胞相比,工程化G115+A12T细胞对PAg呈现的K562细胞表现出增强的细胞分解活性.
- 修改后的T细胞成功地杀死了PAg表达和αvβ6表达的瘤细胞,表明了双重特异性.
- 观察到IFN-γ在任何向抗原激活后释放,这证实了T细胞的反应性.
- 结果强调了CDR3 δ2区域长度对于最佳的PAg识别的重要性.
结论:
- 将瘤结合质插入G115 γδ TCR CDR3 δ2区域扩大了其癌症特异性.
- 使用G115+A12T细胞的新型双特异性方法为癌症免疫治疗提供了一个有希望的策略.
- 这种工程T细胞方法将PAg识别与瘤特异性整合素的向相结合,以改善癌细胞的杀死.
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