Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma

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 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.