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在癌症免疫治疗中准GITR - 没有完美的知识

Diwakar Davar^1,2, Roberta Zappasodi^3,4

¹Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA 15232, USA.

|June 19, 2023

概括

葡萄糖皮质醇诱导的TNFR相关蛋白 (GITR) 激动剂通过增强免疫反应,在癌症免疫疗法中表现有前途. 然而,临床结果令人失望,可能是由于抗体特征影响了疗效.

科学领域:

免疫学免疫学免疫学
癌症免疫疗法癌症免疫疗法
分子生物学分子生物学

背景情况:

葡萄糖皮质醇诱导的TNFR相关蛋白 (GITR) 是TNFR超级家族的一员,对调节获得和先天免疫力至关重要.
GITR在像调节性T细胞 (Tregs) 和自然杀手 (NK) 细胞这样的免疫细胞上表达,影响免疫反应.
它在促进T效应因子功能和抑制Treg介导抑制方面的作用使得GITR成为癌症免疫治疗的重要目标.

研究的目的:

探索GITR激活剂作为癌症免疫治疗策略的潜力.
分析有希望的临床前数据和令人失望的临床结果之间的差异.
研究抗体结构,价值和Fc功能对抗瘤疗效的影响.

主要方法:

在癌症模型中对GITR激动剂进行临床前研究的综述.
对GITR激动剂的临床试验数据的分析.
对抗体依赖细胞细胞毒性 (ADCC) 和其他效应因子功能的机制性研究.
探索GITR激动剂的结构-活性关系.

主要成果:

临床前研究表明,GITR激动剂具有强大的抗瘤功效,无论是单一治疗还是与PD-1阻断等药物结合使用.
使用多种GITR激动剂的临床试验产生了令人失望的结果,与临床前发现形成鲜明对比.
新兴的机制性见解表明,抗体特征 (结构,价值,Fc功能) 在调解抗瘤效应方面发挥着关键作用.

结论:

由于其免疫刺激性质,GITR仍然是癌症免疫治疗的有吸引力的目标.
GITR激动剂的临床前和临床疗效之间的不一致性可以通过抗体特异性机制来解释.
对抗体设计和Fc工程的进一步研究对于优化GITR向癌症疗法至关重要.

关键词:

癌症癌症癌症癌症癌症细胞毒性T淋巴细胞抗原-4 (CTLA-4)葡萄糖皮质醇诱导的TNFR相关蛋白 (GITR)免疫疗法免疫疗法编程死亡-1 (PD-1) 程序化死亡-1 (PD-1) 程序化死亡-1 (PD-1) 程序化死亡

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