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