Uncovering the mechanism of neoadjuvant Vidutolimod and Nivolumab for the treatment of melanoma using multi-omicsMorrison, Robert M (2025) Uncovering the mechanism of neoadjuvant Vidutolimod and Nivolumab for the treatment of melanoma using multi-omics. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractIntratrumoral injections of the TLR9 agonist Vidutolimod (Vidu) combined with the anti-PD-1 Nivolumab has the potential to improve patient outcomes. A single-arm phase II clinical trial of neoadjuvant Vidutolimod combined with Nivolumab in high-risk resectable melanoma demonstrated a major pathologic response (MPR) rate of 55% in 31 evaluable patients. The tumor microenvironment and peripheral circulating immune cells were evaluated using a multi-omics approach that included scRNASeq, scTCRSeq, and spatial transcriptomics. Post-treatment samples from MPR patients showed increased infiltration of pDCs and immune cells with elevated necrosis and melanophagocytosis in the tumor bed. MPR was associated with an elevated post-treatment gene signature of CD8+ T cells, pDCs, myeloid cells, phagocytosis, and macrophage activation. A distinct pre-treatment gene signature for myeloid cells was observed in tumor of MPR patients. Spatial transcriptomics demonstrated a myeloid and macrophage activation gene signature that was elevated in necrosis and histocyte rich regions. In addition, a signature of activated tertiary lymphoid structure (TLS) observed using spatial transcriptomics was elevated due to treatment in bulk RNASeq samples of Vidu/Nivo MPR patients. MPR patients showed elevated CD8+ tumor-infiltrating lymphocytes (TILs) by IHC. ScRNAseq revealed a subset of CD8+ TILs associated with MPR that highly expresses cytotoxicity and MHC class II genes. A similar subset of MPR post-treatment enriched MHC Class II expressing CD8+ T cells was observed in the scRNASeq of PBMC samples. A subset of PBMC Ki67+CD8+ T cells expressing HLA-DR was also elevated in MPRs on-treatment by flow cytometry. This work supports the finding that combined intratumoral injections of vidutolimod with nivolumab produces a broad anti-tumor immune response. Vidu/Nivo strongly activates B cells and macrophages in human melanoma in addition to the previously established pDC activation. This new information may prove critical for the further development of TLR9 agonists like Vidu as a treatment for melanoma and other cancers. Share
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