小细胞肺癌低剂量放疗配合免疫治疗的临床前研究和II期试验。
Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.
发表日期：2024 Jul 02
作者：
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
来源：
Stem Cell Research & Therapy
摘要：
免疫检查点抑制剂 (ICIs) 对广泛期小细胞肺癌 (ES-SCLC) 的疗效有限，但效果并不令人满意。制定治疗 ES-SCLC 的策略至关重要。我们初步探讨了挽救性低剂量放疗 (LDRT) 联合 ICI 对难治性 SCLC 患者的疗效。接下来，我们评估了小鼠 SCLC 的组合疗效。分析肿瘤免疫微环境（TIME）以进行机制研究。随后，我们进行了一项多中心、前瞻性 II 期试验，对初治 ES-SCLC 患者同时进行胸部 LDRT 加化学免疫治疗（MATCH 试验，NCT04622228）。主要终点是确定的客观缓解率 (ORR)，关键次要终点包括无进展生存期 (PFS) 和安全性。对 15 名接受 LDRT 加 ICI 治疗的难治性 SCLC 患者进行回顾性评价。 ORR 为 73.3%（95% 置信区间 [CI]，44.9-92.2）。我们确定了特定剂量的 LDRT（15 Gy/5 次），与 ICI 联合使用时，可显示小鼠 SCLC 生长迟缓并提高生存率。这种组合从肿瘤引流淋巴结中招募了一种特殊的 T 细胞群，TCF1 PD-1 CD8 干样 T 细胞，进入 TIME。 MATCH 试验显示确认的 ORR 为 87.5%（95% CI，75.9-94.8）。中位 PFS 为 6.9 个月（95% CI，5.4-9.3）。这些结果证实 LDRT 联合化学免疫治疗对于 ES-SCLC 是安全、可行和有效的，值得进一步研究。这项研究由华西医院资助（编号：2017）。 ZYJC21003）、国家自然科学基金项目（No. 82073336），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。版权所有©2024作者（ s）。由爱思唯尔公司出版。保留所有权利。
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.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.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).These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation.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).Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.