Cancer Cell | Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma

This study evaluated the neoadjuvant treatment efficacy of the TLR9 agonist Vidutolimod combined with the PD-1 inhibitor Nivolumab in patients with high-risk resectable melanoma, demonstrating a major pathological response (MPR) rate of 55%. It also revealed unique tumor microenvironment and gut microbiome characteristics associated with MPR, providing new biomarkers and a potential predictive model for melanoma immunotherapy.

 

Literature Overview
This article, 'Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma', published in the journal Cancer Cell, reviews and summarizes the application of combined TLR9 agonist and PD-1 inhibitor therapy in melanoma. Using multi-omics analysis and machine learning methods, the study uncovered the tumor microenvironment and gut microbiome features associated with major pathological responses, offering potential predictive tools for optimizing future immunotherapy regimens.

Background Knowledge
Melanoma is a highly malignant skin tumor, and the prognosis for patients with advanced disease remains poor. While PD-1 inhibitors have significantly improved survival rates in melanoma patients, a substantial proportion still do not respond to treatment. TLR9 agonists promote anti-tumor immune activation by stimulating plasmacytoid dendritic cells (pDCs) and inducing type I interferon. This study aims to evaluate the efficacy and mechanisms of Vidutolimod (TLR9 agonist) combined with Nivolumab (PD-1 inhibitor) in neoadjuvant treatment of high-risk melanoma patients, focusing particularly on immune activation within the tumor microenvironment, peripheral T cell proliferation, and gut microbiome characteristics. Using GeoMX DSP, Visium spatial transcriptomics, flow cytometry, and metagenomic sequencing, the study systematically identified biomarkers associated with treatment response, providing potential predictive tools for personalized immunotherapy.

 

 

Research Methods and Experiments
The study enrolled 31 evaluable patients with stage III melanoma who received combined treatment with Vidutolimod and Nivolumab. Immunohistochemistry, flow cytometry, GeoMX DSP, Visium spatial transcriptomics, and metagenomic sequencing were used to evaluate changes in the tumor microenvironment, peripheral immune cells, and gut microbiome. Additionally, a random forest machine learning model was employed to predict the likelihood of major pathological response (MPR).

Key Conclusions and Perspectives

• MPR patients showed increased intratumoral infiltration of CD8+ T cells and plasmacytoid dendritic cells (pDCs), along with elevated frequencies of peripheral Ki67+CD8+ T cells following treatment
• The tumor microenvironment of MPR patients exhibited enrichment in myeloid cell populations, phagocytic activity, and macrophage activation gene signatures
• MPR patients had enrichment of Gram-negative bacterial families such as Bacteroidaceae and Enterobacteriaceae, whereas non-MPR patients showed increased Gram-positive bacteria like Lachnospiraceae
• Machine learning models based on gene expression or microbiome data could effectively predict MPR, with AUC values of 0.64 and 0.68, respectively

Research Significance and Prospects
The study provides potential immune and microbiome biomarkers for melanoma neoadjuvant therapy, supporting the synergistic role of TLR9 agonists and PD-1 inhibitors in activating anti-tumor immunity. Future studies should include larger randomized controlled trials to validate these findings and explore the application of gut microbiota modulation in enhancing immunotherapy response.

 

 

Conclusion
This study systematically analyzed the immune activation mechanisms and gut microbiome features associated with combination TLR9 agonist and PD-1 inhibitor therapy in melanoma, identifying distinct immune cell infiltration patterns and microbiome compositions in MPR patients. These findings provide potential predictive markers for optimizing melanoma immunotherapy and suggest that gut microbiota may serve as a target for personalized treatment. The results highlight the importance of both local tumor microenvironment and systemic immune activation in therapeutic response, offering mechanistic insights for future combination immunotherapy strategies.

 

Diwakar Davar, Robert M Morrison, Amiran K Dzutsev, Giorgio Trinchieri, and Hassane M Zarour. Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma: A Prospective Phase II trial. Cancer cell.