Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Med Pub Date : 2024-10-11 Epub Date: 2024-07-03 DOI:10.1016/j.medj.2024.06.002

Hui Wang, Zhuoran Yao, Kai Kang, Lin Zhou, Weigang Xiu, Jianguo Sun, Conghua Xie, Min Yu, Yanying Li, Yan Zhang, Yue Zheng, Guo Lin, Xiangyu Pan, Yijun Wu, Ren Luo, Laduona Wang, Min Tang, Shuangsi Liao, Jiang Zhu, Xiaojuan Zhou, Xuanwei Zhang, Yong Xu, Yongmei Liu, Feng Peng, Jin Wang, Lisha Xiang, Limei Yin, Lei Deng, Meijuan Huang, Youling Gong, Bingwen Zou, Hui Wang, Lin Wu, Zhiyong Yuan, Nan Bi, Min Fan, Yaping Xu, Ruizhan Tong, Linglu Yi, Lu Gan, Jianxin Xue, Xianming Mo, Chong Chen, Feifei Na, You Lu

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Abstract

Background: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical.

Methods: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety.

Findings: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1⁺ PD-1⁺ CD8⁺ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3).

Conclusions: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation.

Funding: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

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小细胞肺癌低剂量放射治疗与免疫治疗的临床前研究和 II 期试验。

背景：免疫检查点抑制剂（ICIs）对广泛期小细胞肺癌（ES-SCLC）的治疗效果一般，但并不令人满意。制定治疗ES-SCLC的策略至关重要：我们初步探讨了低剂量放疗（LDRT）加 ICI 对难治性 SCLC 患者的挽救效果。接下来，我们在小鼠 SCLC 中评估了联合疗法的疗效。我们对肿瘤免疫微环境（TIME）进行了机理分析。随后，我们开展了一项多中心、前瞻性的II期试验，对治疗无效的ES-SCLC患者同时进行胸部LDRT加化疗免疫疗法（MATCH试验，NCT04622228）。主要终点是确诊客观反应率（ORR），关键次要终点包括无进展生存期（PFS）和安全性：对15例接受LDRT加ICI治疗的难治性SCLC患者进行了回顾性研究。ORR为73.3%（95%置信区间[CI]，44.9-92.2）。我们确定了一种特定剂量的 LDRT（15 Gy/5次），这种剂量的 LDRT 与 ICIs 联用时可延缓生长并提高小鼠 SCLC 的存活率。这种组合可将肿瘤引流淋巴结中的特殊T细胞群--TCF1+ PD-1+ CD8+干样T细胞--招募到TIME中。MATCH 试验显示，确诊 ORR 为 87.5%（95% CI，75.9-94.8）。中位PFS为6.9个月（95% CI，5.4-9.3）：这些研究结果验证了LDRT加化疗免疫治疗对ES-SCLC是安全、可行和有效的，值得进一步研究：本研究得到了华西医院（编号：ZYJC21003）、国家自然科学基金（编号：82073336）的资助，MATCH试验得到了罗氏（中国）控股有限公司（RCHL）和上海罗氏制药有限公司（RCHL）的全额资助。(MATCH试验由罗氏（中国）控股有限公司（RCHL）和上海罗氏制药有限公司（SRPL）全额资助。(MATCH试验由罗氏（中国）控股有限公司和上海罗氏制药有限公司全额资助。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.