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, Hassane M. Zarour
{"title":"新辅助维杜莫德和 nivolumab 治疗高风险可切除黑色素瘤:前瞻性 II 期试验","authors":"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, Hassane M. Zarour","doi":"10.1016/j.ccell.2024.10.007","DOIUrl":null,"url":null,"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<sup>+</sup> tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67<sup>+</sup>CD8<sup>+</sup> 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. 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Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial
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.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.