Clinical Trial

. 2024 Nov 11;42(11):1898-1918.e12.

doi: 10.1016/j.ccell.2024.10.007. Epub 2024 Oct 31.

Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial

Diwakar Davar¹, Robert M Morrison², Amiran K Dzutsev³, Arivarasan Karunamurthy⁴, Joe-Marc Chauvin⁵, Florent Amatore⁶, Julie S Deutsch⁷, Rodrigo X Das Neves⁶, Richard R Rodrigues⁸, John A McCulloch⁹, Hong Wang¹⁰, Douglas J Hartman¹¹, Jonathan H Badger⁹, Miriam R Fernandes³, Yulong Bai¹², Jie Sun¹², Alicia M Cole³, Poonam Aggarwal³, Jennifer R Fang³, Christopher Deitrick⁵, Riyue Bao⁶, Umamaheswar Duvvuri¹³, Shaum S Sridharan¹³, Seungwon W Kim¹³, Haroon A Choudry¹⁴, Matthew P Holtzman¹⁴, James F Pingpank¹⁴, James Patrick O'Toole¹⁵, Richelle DeBlasio⁵, Yang Jin⁵, Quanquan Ding⁵, Wentao Gao⁵, Christopher Groetsch⁵, Ornella Pagliano⁵, Amy Rose⁵, Corey Urban⁵, Jagjit Singh¹¹, Prajan Divarkar¹⁶, David Mauro¹⁷, Dmitri Bobilev¹⁷, James Wooldridge¹⁷, Arthur M Krieg¹⁷, Matthew G Fury¹⁸, Jeffrey R Whiteaker¹⁹, Lei Zhao¹⁹, Amanda G Paulovich¹⁹, Yana G Najjar⁶, Jason J Luke⁶, John M Kirkwood⁶, Janis M Taube²⁰, Hyun Jung Park²¹, Giorgio Trinchieri²², Hassane M Zarour²³

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: davard@upmc.edu.
² Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
³ Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
⁷ Division of Dermatopathology, Johns Hopkins University, Baltimore, MD, USA.
⁸ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁹ Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
¹² Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁵ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Division of Plastic Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Nanostring Technologies, Seattle, WA, USA.
¹⁷ Checkmate Pharmaceuticals, Cambridge, MA, USA.
¹⁸ Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.
¹⁹ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁰ Division of Dermatopathology, Johns Hopkins University, Baltimore, MD, USA; Tumor Microenvironment Core, Bloomberg-Kimmel Institute of Immunotherapy, Mark Foundation Center for Advanced Imaging and Genomics, Johns Hopkins University, Baltimore, MD, USA.
²¹ Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
²² Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: trinchig@mail.nih.gov.
²³ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: zarourhm@upmc.edu.

PMID: 39486411
PMCID: PMC11560503 (available on 2025-11-11)
DOI: 10.1016/j.ccell.2024.10.007

Clinical Trial

Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial

Diwakar Davar et al. Cancer Cell. 2024.

. 2024 Nov 11;42(11):1898-1918.e12.

doi: 10.1016/j.ccell.2024.10.007. Epub 2024 Oct 31.

Authors

Affiliations

¹ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: davard@upmc.edu.
² Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
³ Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA.
⁷ Division of Dermatopathology, Johns Hopkins University, Baltimore, MD, USA.
⁸ Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA; Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁹ Genetics and Microbiome Core, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
¹² Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
¹³ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Division of Surgical Oncology, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁵ University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Division of Plastic Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁶ Nanostring Technologies, Seattle, WA, USA.
¹⁷ Checkmate Pharmaceuticals, Cambridge, MA, USA.
¹⁸ Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA.
¹⁹ Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²⁰ Division of Dermatopathology, Johns Hopkins University, Baltimore, MD, USA; Tumor Microenvironment Core, Bloomberg-Kimmel Institute of Immunotherapy, Mark Foundation Center for Advanced Imaging and Genomics, Johns Hopkins University, Baltimore, MD, USA.
²¹ Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
²² Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: trinchig@mail.nih.gov.
²³ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA; Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: zarourhm@upmc.edu.

PMID: 39486411
PMCID: PMC11560503 (available on 2025-11-11)
DOI: 10.1016/j.ccell.2024.10.007

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.

Keywords: ICI; PD-1; TLR9; immunotherapy; innate agonist; macrophage; melanoma; neoadjuvant; pDC; vidutolimod.

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Conflict of interest statement

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), steering committee membership (Immunocore, Replimmune) and 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.N. 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.G.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.

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Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial

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Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial

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