Zhang Yiran, Guan Hanyang, Liu Shijin, Li Haoquan, Bian Zili, He Jiashuai, Zhao Zhan, Qiu Shenghui, Mo Tianmu, Zhang Xiangwei, Chen Zuyang, Ding Hui, Zhao Xiaoxu, Wang Liang, Pan Yunlong, Pan Jinghua
Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Department of Body Gamma Knife, The First Affiliated Hospital of Jinan University, Guangzhou, China.
Elife. 2025 Jun 26;14:RP103559. doi: 10.7554/eLife.103559.
An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.
In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.
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.
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.
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).
ChiCTR2200066117.
免疫抑制性肿瘤微环境限制了免疫治疗的疗效，因此微卫星稳定（MSS）和错配修复缺陷（pMMR）的转移性结直肠癌（mCRC）患者常常面临巨大挑战。
在这项II期试验中，患者接受了伽玛刀立体定向体部放疗（SBRT）联合替雷利珠单抗治疗。在治疗前和治疗后进行生物标志物分析。
2022年11月至2024年7月，20例患者中1例达到完全缓解（CR），13例达到部分缓解（PR），6例疾病稳定（SD）。中位无进展生存期（mPFS）为10.7个月（95%置信区间，6.4 - 15.0）。未观察到4级事件，常见的不良事件包括恶心（65%）、贫血（55%）和疲劳（45%）。RNA测序表明PR患者的免疫浸润增强。对于一线和二线治疗无效的pMMR/MSS/MSI-L mCRC患者，伽玛刀SBRT联合替雷利珠单抗显示出高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有显著改善，包括纤维化降低、肿瘤血管正常化以及PD-1/PD-L1检查点通路激活。
这些结果表明，对于一线和二线化疗无效的pMMR/MSS/MSI-L mCRC患者，伽玛刀SBRT联合替雷利珠单抗提供了一种安全有效的后线治疗选择。
本研究得到暨南大学附属第一医院临床前沿技术项目（编号：JNU1AF-CFTP-2022-a01223）、国家自然科学基金（82204436）、广东省自然科学基金（2024A1515030010、2022A1515011695）、广州市科技项目（2024A03J0825）的支持。
ChiCTR2200066117
