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