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Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma

SSRN, ISSN: 1556-5068
2024
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    322
    • Abstract Views
      305
    • Downloads
      17

Article Description

Intratumoral TLR9 agonists and anti-PD-1 therapies provide durable clinical responses and broad immune activation. To evaluate the efficacy and mechanisms of action of this therapeutic combination, we conducted a single-arm phase 2 neoadjuvant study of TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in patients with high-risk resectable melanoma. In 31 evaluable patients, 55% (17/31) had major pathologic response (MPR), with eight grade 3 treatment-related adverse events. 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+ and Ki67+ CD4+ T cells, pDCs, and monocytes peripherally. Patients with MPR 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. Patients with MPR also had gut microbial signatures 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 antitumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiome composition. Trial Registration Details: ClinicalTrials.gov NCT03618641 Funding Information: The study was funded by Checkmate Pharmaceuticals, which supplied investigational product vidu. Nivo was purchased via commercial insurance. Declaration of Interests: D.D. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. D.D. also reports grants/research support (Arcus, Immunocore, Merck, Regeneron Pharmaceuticals Inc., Tesaro/GSK.), consulting [ACM Bio, Ascendis, Castle, Clinical Care Options (CCO), Gerson Lehrman Group (GLG), Immunitas, Medical Learning Group (MLG), Replimmune, Trisalus, Xilio Therapeutics], speakers' bureau (Castle Biosciences) and provisional patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work. P.D. is currently employed by Nanostring Technologies and reports stock options. Y.G.J. reports grants/research support (Bristol-Myers Squibb, Merck Sharp & Dohme and Pfizer) and consulting (Checkmate Pharmaceuticals) outside the submitted work. J.J.L. reports grants/research support (multiple), membership on data safety monitoring boards (multiple), membership on scientific advisory boards with no stock ownership or stock options (multiple), membership on scientific advisory boards with stock for (multiple), consulting (multiple) and a provisional patent for cancer immunotherapy (PCT/US18/36052: Microbiome Biomarkers for anti-PD-1/PD-L1 responsiveness: diagnostic, prognostic and therapeutic uses thereof) all outside the submitted work. D.M. is currently employed by Codiak Biosciences and reports stock options. D.B., J.W. and A.K. were formerly employed by CheckMate and report stock options. M.F. is currently employed by Regeneron Pharmaceuticals Inc. and reports stock options. J.M.K. reports grants/research support (Bristol-Myers Squibb, Amgen Inc.) and consulting (Bristol-Myers Squibb, Checkmate Pharmaceuticals, Novartis, Amgen Inc., Checkmate, Castle Biosciences, Inc., Immunocore LLC, Iovance, Novartis.) outside the submitted work. J.M.T. reports grants and consulting from Bristol-Myers Squibb, Merck Sharp & Dohme, Astra Zeneca, and Compugen outside the submitted work. H.M.Z. reports grants/research support (NIH/NCI and Checkmate Pharmaceuticals) and consulting (Checkmate Pharmaceuticals) during the conduct of the study. H.M.Z. also reports grants/research support (NIH/NCI, Bristol-Myers Squibb and GlaxoSmithKline), personal fees (GlaxoSmithKline, Bayer, and Vedanta) and pending provisional patents related to gut microbial signatures of response and toxicity to immune checkpoint blockade (US Patent 63/124,231 and US Patent 63/208,719) outside the submitted work. The remaining authors have no conflicts to declare. Ethics Approval Statement: The trial was approved by the University of Pittsburgh Institutional Review Board (#MOD19040237-015). The trial was conducted in accordance with ethical principles of the Declaration of Helsinki and with adherence to Good Clinical Practice guidelines, as defined by the International Conference on Harmonization. This protocol was conducted in compliance with all relevant ethical regulations. Written informed consent was obtained from all participants. The Hillman Cancer Center Data Safety Monitoring Board reviewed data every 12 months.

Bibliographic Details

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; Jonathan H. Badger; Douglas J. Hartman; Miriam R. Fernandes; Yulong Bai; Jie Sun; Alicia M. Cole; Poonam Aggarwal; Jennifer R. Fang; Christopher Deitrick; Riyue Bao; Umamaheswar Duvvuri; Shaum S. Sridharan; Seungwon W. Kim; M. Haroon Asif 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 Wooldridge; Art 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

Elsevier BV

Multidisciplinary; melanoma; resectable; neoadjuvant; TLR; innate; PD-1; PD1; CTLA-4; CTLA4

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