| Autor: |
Diwakar Davar, Arivarasan Karunamurthy, Joe-Marc Chauvin, Robert Morrison, Yulong Bai, Jie Sun, Julie Stein, Richard Rodrigues, John McCulloch, Hong Wang, Douglas Hartman, Miriam Fernandes, Alicia Cole, Amiran Dzutsev, Christopher Deitrick, Riyue Bao, Umamaheswar Duvvuri, Shaum Sridha, Seungwon Kim, M. Haroon Choudry, Matthew Holtzman, James Pingpank, James O'Toole, Richelle DeBlasio, Yang Jin, Quanquan Ding, Wentao Gao, Christopher Groetsch, Ornella Pagliano, Amy Rose, Corey Urban, Jagjit Singh, Prajan Divakar, David Mauro, Dmitri Bobilev, James Wooldridge, Arthur Krieg, Matthew Fury, Yana Najjar, Jason Luke, John Kirkwood, Janis Taube, Hyun Jung Park, Giorgio Trinchieri, Hassane Zarour |
| Rok vydání: |
2022 |
| DOI: |
10.21203/rs.3.rs-2235839/v1 |
| Popis: |
Intratumoral TLR9 agonists and anti-PD-1 provide durable clinical responses and broad immune activation. To evaluate efficacy and mechanisms of action of this combined treatment, we conducted a single-arm phase 2 neoadjuvant study of TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab (vidu/nivo) in patients with high-risk resectable melanoma. In 30 evaluable patients, 57% (17/30) had major pathologic response (pR), with eight grade 3 treatment-related adverse events. pR was associated with lower residual viable tumor, necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment and increased frequencies of Ki67+ CD8+ and CD4+ T cells, pDCs, and monocytes peripherally. Gene signatures associated with pR included increased pDC density, macrophage activation, and phagocytosis engulfment. Gut microbial signatures in pR were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and to the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidu/nivo treatment stimulates a broad antitumor immune response and is associated with a distinct baseline gut microbiome composition. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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