美国匹兹堡大学Hassane M. Zarour等研究人员合作完成新辅助vidutolimod和nivolumab用于高风险可切除黑色素瘤的前瞻性II期试验。该研究于2024年10月31日在线发表于国际一流学术期刊《癌细胞》。

研究人员进行了一项单臂研究，评估新辅助TLR9激动剂vidutolimod与抗PD-1 nivolumab联合用于高风险可切除黑色素瘤的疗效。在31名可评估患者中，观察到55%的主要病理反应（MPR），符合主要终点。MPR与坏死相关，并伴有黑色素细胞吞噬现象，同时肿瘤微环境中CD8⁺肿瘤浸润淋巴细胞和浆细胞样树突细胞（pDC）增加，外周Ki67⁺CD8⁺ T细胞的频率增加。MPR患者在治疗前的基因特征显示出富集的髓系细胞基因特征，且对治疗的反应与免疫细胞、pDC、吞噬作用和巨噬细胞激活的基因特征相关。MPR患者的肠道微生物群中富含属于拟杆菌科和肠杆菌科的革兰氏阴性细菌，以及一小部分革兰氏阴性厚壁菌。

这些研究结果支持联合使用vidutolimod和nivolumab能够刺激广泛的抗肿瘤免疫反应，并与独特的基础髓系基因特征和肠道微生物群相关。临床试验注册号为NCT03618641。

研究人员表示，肿瘤内TLR9激动剂和抗PD-1治疗产生临床反应和广泛的免疫激活。

附：英文原文

Title: Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial

Author: Diwakar Davar, Robert M. Morrison, Amiran K. Dzutsev, Arivarasan Karunamurthy, Joe-Marc Chauvin, Florent Amatore, Julie S. Deutsch, Rodrigo X. Das Neves, Richard R. Rodrigues, John A. McCulloch, Hong Wang, Douglas J. Hartman, Jonathan H. Badger, Miriam R. Fernandes, Yulong Bai, Jie Sun, Alicia M. Cole, Poonam Aggarwal, Jennifer R. Fang, Christopher Deitrick, Riyue Bao, Umamaheswar Duvvuri, Shaum S. Sridharan, Seungwon W. Kim, Haroon A. Choudry, Matthew P. Holtzman, James F. Pingpank, James Patrick OToole, Richelle DeBlasio, Yang Jin, Quanquan Ding, Wentao Gao, Christopher Groetsch, Ornella Pagliano, Amy Rose, Corey Urban, Jagjit Singh, Prajan Divarkar, David Mauro, Dmitri Bobilev, James Wooldridge, Arthur M. Krieg, Matthew G. Fury, Jeffrey R. Whiteaker, Lei Zhao, Amanda G. Paulovich, Yana G. Najjar, Jason J. Luke, John M. Kirkwood, Janis M. Taube, Hyun Jung Park, Giorgio Trinchieri, Hassane M. Zarour

Issue&Volume: 2024-10-31

Abstract: Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+CD8+ T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.

DOI: 10.1016/j.ccell.2024.10.007

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00395-7