在治疗AVELUMAB和免疫刺激剂组合后,瘤微环境的变化发生在患有晚期固体瘤的患者中
Research square
|February 6, 2026
概括
将免疫检查点抑制剂与抗OX40和抗-4-1BB等激动剂结合起来,可以克服固体瘤中的抗性. 这项研究探讨了组合疗法,揭示了对免疫反应调节和患者益处的见解. 需要进一步的研究来增强抗瘤免疫力.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 癌症基因组学 癌症基因组学
背景情况:
- 免疫检查点抑制剂 (ICI) 已经彻底改变了癌症治疗,但在初级和获得性耐药性方面面临挑战.
- 研究ICI与免疫刺激激动剂 (anti-OX40,anti-4-1BB) 的新组合对于克服抗性至关重要.
- 了解这些组合对瘤微环境和免疫反应的影响,是增强固体瘤抗瘤免疫力的关键.
研究的目的:
- 为了评估结合阿维卢马布 (ICI) 与免疫刺激激动剂 (4-1BB和/或OX40激动剂) 或放射治疗的治疗影响.
- 分析这些组合疗法后瘤微环境和免疫反应的变化.
- 确定高级固体瘤患者临床益处的基因组和免疫相关物.
主要方法:
- 一个I/II期临床试验 (NCT03217747),涉及四个治疗臂:阿维卢马布与乌托米卢马布,阿维卢马布与PF-04518600,阿维卢马布与两种激动剂,以及阿维卢马布与放射治疗.
- 使用全外体序列 (WES),大量RNAseq,多重免疫光学 (mIF) 和染色体免疫组织化学 (IHC) 进行瘤组织的综合分析.
- 进行了纵向外周血流细胞计,以监测免疫细胞的变化.
主要成果:
- 观察到低瘤突变负担 (TMB < 6) 和RTK-RAS,TP53,PI3K和WNT通路的变化.
- 鉴定了TP53,TTN,KRAS中的突变以及PIK3CA,CCNE1和KRAS中的拷贝数变异.
- 在联合激动剂手臂 (C手臂) 中,在结直肠和胰腺癌的治疗中,早期观察到干扰素-马信号通路的丰富. 有临床益处的患者表现出更高的基线和在治疗中的T细胞频率.
结论:
- 组织学子集之间存在基因组差异,与治疗结果相关.
- 结合策略是必要的,以增强抗瘤T细胞的招募和初始化.
- 解决免疫不容许的瘤状态对于改善晚期固体瘤对免疫治疗的反应至关重要.
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