A novel combination of vidutolimod, a toll-like receptor 9 (TLR9) agonist, and nivolumab, a PD-1 checkpoint inhibitor, has shown significant promise in treating advanced melanoma. A phase II clinical trial, led by researchers at the University of Pittsburgh, UPMC Hillman Cancer Center, and the National Cancer Institute (NCI), demonstrated a 55% response rate in patients with stage III cutaneous melanoma when the drug combination was administered prior to surgery.
Trial Details and Findings
The trial involved 31 patients with high-risk stage III resectable melanoma who received seven injections of vidutolimod into their tumors and three rounds of intravenous nivolumab before undergoing surgery. Following surgery, patients continued to receive both drugs every four weeks for one year. The primary endpoint was the pathological response rate, defined as the percentage of patients with less than 10% viable tumor cells remaining in the surgical specimen after pre-surgical therapy.
The results, published in Cancer Cell, revealed that 55% of patients achieved this high level of response. Furthermore, patients exhibiting the highest response rates demonstrated impressive two-year recurrence-free survival (88%) and metastasis-free survival rates (94%).
Mechanism of Action
Researchers investigated the underlying mechanisms driving the observed responses by comparing tumors and blood samples from high-responding patients to those who responded less effectively. The analysis revealed that plasmacytoid dendritic cells (pDCs) and myeloid cells were enriched in the tumors of high-responding patients. These cells are known to augment T cell-mediated anti-tumor immunity, suggesting that vidutolimod stimulates anti-tumor immunity in a unique way.
Diwakar Davar, MD, clinical director for the Melanoma and Skin Cancer Program at UPMC Hillman, noted, "This is the first and only clinical trial so far to test the novel combination of nivolumab and the experimental drug vidutolimod in the neoadjuvant setting. It’s exciting that we saw a response rate of 55%, which is on par with currently approved immunotherapy combinations."
Vidutolimod and TLR9
Vidutolimod targets the TLR9 pattern recognition receptor, a protein crucial for initiating innate immune responses to foreign threats. TLR9-targeting agents are often included in drugs and vaccines due to their immune-augmenting effects. The study's findings suggest that vidutolimod, in combination with nivolumab, can effectively convert the tumor microenvironment from uninflamed to inflamed, thereby enhancing T cell-mediated anti-tumor immunity.
Gut Microbiome Analysis
The research team also analyzed the gut microbiome of the patients, finding that patients whose tumors shrank the most had higher levels of Gram-negative bacteria. This observation contrasts with some previous studies suggesting that Gram-negative bacteria are not typically associated with response to anti-PD1 therapy.
Future Directions
Vidutolimod is currently being evaluated in multiple indications, including melanoma, cutaneous malignancies, non-small cell lung cancer, and prostate cancer. These ongoing studies aim to further elucidate the potential of vidutolimod as a therapeutic agent in various cancer types.
