A novel immunotherapy combination of vidutolimod and nivolumab has demonstrated promising results in patients with stage 3 cutaneous melanoma. The single-arm phase 2 clinical trial, led by researchers at the University of Pittsburgh, UPMC Hillman Cancer Center, and the National Cancer Institute (NCI), showed that pre-surgical treatment with the combination led to tumor control in 55% of patients. These findings, published in Cancer Cell, suggest a potential new approach for treating melanoma and offer insights into the mechanism of action of vidutolimod.
Trial Details and Outcomes
The phase 2 trial involved 31 patients with high-risk stage 3 resectable melanoma. Patients received seven injections of vidutolimod into their tumors and three rounds of intravenous nivolumab before undergoing surgery. Following surgery, they continued to receive both drugs every four weeks for one year. The primary endpoint was the proportion of patients achieving a pathological response, defined as less than 10% viable tumor cells remaining in the surgical specimen after pre-surgical therapy.
The results showed that 55% of patients achieved this high response rate. Furthermore, patients with the highest response rate to the combination therapy had an impressive two-year recurrence-free survival rate of 88% and a metastasis-free survival rate of 94%. The remaining 45% of patients had either partial (10-50% viable tumor) or no response (>50% viable tumor).
Immunological Insights
Further analysis revealed that patients with high response rates had an enrichment of plasmacytoid dendritic cells (pDCs) and myeloid cells in their tumors compared to those who responded poorly. According to Dr. Diwakar Davar, associate professor at the Pitt School of Medicine and UPMC Hillman, these cells are not typically enriched in patients treated with nivolumab alone, suggesting that vidutolimod stimulates anti-tumor immunity through a unique mechanism.
Pharmacodynamic Marker Identification
Researchers, including Amanda Paulovich, M.D., of Fred Hutch Cancer Center, used mass spectrometry to demonstrate that most patients treated with vidutolimod and nivolumab had higher levels of key immune-related proteins. This suggests that unique signatures of TLR9 activation underlie the drugs' activity. "For any drug, it’s important to be able to measure proteins or markers that indicate whether a drug is working or not, which is known as a pharmacodynamic response," said Davar.
Gut Microbiome Influence
Interestingly, the study also found a correlation between the gut microbiome composition and treatment response. Patients whose tumors shrank the most had higher levels of Gram-negative bacteria, which is not typically associated with response to anti-PD1 therapy. "Our data suggest that the mechanisms by which the gut microbiome modulates responses to cancer immunotherapy may differ depending on the specific therapy," explained Dr. Hassane Zarour, professor at the Pitt School of Medicine and UPMC Hillman.
Implications for Melanoma Treatment
The findings from this trial support the further development of vidutolimod for treating cutaneous melanoma. The combination of vidutolimod and nivolumab shows promise as a neoadjuvant therapy, potentially improving long-term outcomes for patients with high-risk resectable melanoma. The identification of a potential pharmacodynamic marker for TLR9 agonists could also aid in the development of future immunotherapies.
