More than half of patients with advanced melanoma responded to a new drug combination in a phase II clinical trial led by the University of Pittsburgh, UPMC Hillman Cancer Center, and the National Cancer Institute (NCI). They combined the novel toll-like receptor 9 (TLR9) agonist vidutolimod (vidu) and PD-1 checkpoint inhibitor nivolumab. The patients had stage III cutaneous melanoma and the drug combo was given pre-surgery.
In the patients with the highest response rate to the combination therapy, the two-year recurrence-free survival rate and metastasis-free survival rate was 88% and 94%, respectively.
The team’s findings are published in Cancer Cell and led by Diwakar Davar, MD, clinical director for the Melanoma and Skin Cancer Program, associate professor of medicine in the division of hematology/oncology, and a medical oncologist/hematologist at UPMC Hillman.
Vidu is currently being evaluated in multiple indications, including melanoma, cutaneous malignancies, non-small cell lung cancer, and prostate cancer. This team hypothesized that combining intratumoral vidu and systemic anti-PD-1 would improve upon the benefit of single-agent PD-1 blockade by activating tumor-infiltrating plasmacytoid dendritic cells (pDCs) and converting the tumor microenvironment from uninflamed to inflamed, thus augmenting T cell-mediated anti-tumor immunity.
“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,” said Davar. “It’s exciting that we saw a response rate of 55%, which is on par with currently approved immunotherapy combinations.”
Vidu, which has not yet been approved by the U.S. FDA, targets the TLR9 pattern recognition receptor, which is a protein that plays a critical role in the initiation of innate immune responses to foreign threats. TLR9-targeting agents are often included in drugs and vaccines because of their immune-augmenting effects, but less is known about how they work in combination with other cancer therapies.
For this phase II clinical trial, 31 patients with high-risk stage III resectable melanoma received seven injections of vidu into their tumors and three rounds of intravenous nivolumab prior to surgery. Following surgery, they continued to receive both drugs every four weeks for one year.
After pre-surgical therapy, 55% of patients responded so well that less than 10% of viable tumor cells remained in the surgical specimen, which previous research has shown is a good predictor of long-term survival in melanoma patients. The other 45% of patients had either partial (10–50% viable tumor) or no response (>50% viable tumor).
When the researchers compared tumors and blood from the high responding patients to those who didn’t respond as well, they found that pDCs and myeloid cells were enriched in the former compared to the latter. pDCs augment the ability of T cells to eliminate tumors.
Myeloid cells can suppress immune responses in tumors but can be targeted by multiple agents, including TLR agonists, to augment cancer immunotherapy. Neither pDCs nor myeloid cells are typically enriched in patients treated with nivolumab alone, so these observations suggest that vidu stimulates anti-tumor immunity in a unique way.
The team of investigators also analyzed the gut microbiome of the patients. Notably, patients whose tumors shrank the most had higher levels of Gram-negative bacteria, bacteria that are not usually associated with response to anti-PD1 therapy, according to other studies, including research by Davar and colleagues.
