Gamma Knife stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: a phase II trial analysis.

IF 6.4 1区生物学 Q1 BIOLOGY

eLife Pub Date : 2025-06-26 DOI:10.7554/eLife.103559

Yiran Zhang, Hanyang Guan, Shijin Liu, Haoquan Li, Zili Bian, Jiashuai He, Zhan Zhao, Shenghui Qiu, Tianmu Mo, Xiangwei Zhang, Zuyang Chen, Hui Ding, Xiaoxu Zhao, Liang Wang, Yunlong Pan, Jinghua Pan

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引用次数: 0

Abstract

Background: An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.

Methods: In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.

Results: From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.

Conclusions: These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.

Funding: This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).

Clinical trial number: ChiCTR2200066117.

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伽玛刀立体定向放疗联合tislelizumab作为pMMR/MSS/MSI-L转移性结直肠癌的后期治疗：一项II期试验分析

背景：免疫抑制的肿瘤微环境限制了免疫治疗的效果，因此MSS和pMMR的mCRC患者往往面临很大的挑战。方法：在这项II期试验中，患者接受伽玛刀SBRT联合Tislelizumab。治疗前后分别进行生物标志物分析。结果：2022年11月至2024年7月，20例患者中有1例达到CR， 13例达到PR， 6例达到SD。mPFS为10.7个月（95% CI, 6.4-15.0）。在没有4级事件的情况下，常见的不良事件包括恶心（65%）、贫血（55%）和疲劳（45%）。RNA测序显示PR患者免疫浸润增强。对于一线和二线治疗无效的pMMR/MSS/MSI-L mCRC患者，伽玛刀SBRT联合tislelizumab显示出较高的疗效和合理的安全性。生物标志物分析显示，放疗后肿瘤免疫抑制微环境显著改善，包括纤维化降低、肿瘤血管正常化和PD-1/PD-L1检查点通路的激活。结论：这些结果表明，对一线和二线化疗无反应的pMMR/MSS/MSI-L mCRC患者，伽玛刀SBRT联合tislelizumab提供了一种安全有效的后期治疗选择。基金资助：本研究由暨南大学第一附属医院临床前沿技术计划资助(项目编号：；JNU1AF-CFTP-2022-a01223)，国家自然科学基金项目（82204436），广东省自然科学基金项目（2024a1515030010,2022a1515011695），广州市科技项目（2024A03J0825）。临床试验号：ChiCTR2200066117。

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来源期刊

eLife BIOLOGY-

CiteScore

12.90

自引率

3.90%

发文量

3122

审稿时长

17 weeks

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