Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial
Diwakar Davar, Robert M. Morrison, Amiran Dzutsev, Arivarasan Karunamurthy, Joë-Marc Chauvin, F. 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 Sridharan, Seungwon Kim, Haroon A. Choudry, Matthew P. Holtzman, James F. Pingpank, James Patrick O'Toole, 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 E. Wooldridge, Arthur Μ. 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
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.