Presurgical treatment with the novel drug vidutolimod and the PD-1 checkpoint inhibitor nivolumab may improve tumor control in patients with stage III cutaneous melanoma, according to a recent study published by Davar et al in Cancer Cell. The findings provided insights that could help advance research on and support the development of vidutolimod for the treatment of cutaneous melanoma and other cancer types.
Background
Plasmacytoid dendritic cells 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.
Vidutolimod—which has not yet been approved by the U.S. Food and Drug Administration—targets the TLR9 pattern recognition receptor, 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 as a result of their immune-augmenting effects; however, little is known about how they work in combination with other cancer therapies.
“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,” explained lead study author Diwakar Davar, MD, Associate Professor at the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center. “Prior to this work, we did not have a pharmacodynamic parameter for TLR9 agonists and other innate agonists, so identifying a protein signature associated with TLR9 administration was a key finding,” he continued.
Study Methods and Results
In the single-arm phase II clinical trial, researchers assigned 31 patients with high-risk stage III resectable melanoma to receive seven injections of vidutolimod into their tumors and three rounds of intravenous nivolumab prior to surgery. Following surgery, they continued to receive both drugs every 4 weeks for 1 year.
The treatment combination led to tumor control in 55% of the patients—among whom less than 10% of viable tumor cells remained int eh surgical specimen. Previous research has indicated that this may be a good predictor of long-term survival in patients with melanoma. The other 45% of the patients exhibited either partial (10% to 50% viable tumor cells) or no response (greater than 50% viable tumor cells). Among the patients with the highest response rates to the combination therapy, the 2-year recurrence-free survival rate and metastasis-free survival rate was 88% and 94%, respectively.
After the researchers compared tumors and blood from the patients who responded the highest with those who didn’t respond as well, they found that plasmacytoid dendritic cells and myeloid cells were enriched in the highest responders. Neither plasmacytoid dendritic cells nor myeloid cells are typically enriched in patients treated with nivolumab alone. Therefore, these observations suggested that vidutolimod may stimulate antitumor immunity in a unique way.
The researchers used mass spectrometry to show that most patients treated with vidutolimod and nivolumab had higher levels of key immune-related proteins, revealing that signatures of TLR9 activation could underlie the drugs’ activity.
The researchers also analyzed the study participants’ gut microbiomes. Notably, the patients whose tumors shrank the most had higher levels of Gram-negative bacteria, which are not typically associated with response to anti–PD-1 therapy,
Conclusions
“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,” highlighted Dr. Davar. “It’s exciting that we saw a response rate of 55%, which is on par with currently approved immunotherapy combinations,” he added.
“Our data suggest that the mechanisms by which the gut microbiome modulates responses to cancer immunotherapy may differ depending on the specific therapy,” underscored co–senior study author Hassane Zarour, MD, Professor at the University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center. “Such novel findings highlight the complexity and context-dependency of the gut microbiome’s effects in cancer immunotherapy and have prompted ongoing studies to confirm this observation,” he concluded.
Disclosure: The research in this study was supported by Checkmate Pharmaceuticals, the National Institutes of Health, the Melanoma Research Foundation Breakthrough Consortium Team Science Award, and the Visium Spatial FFPE Challenge Award. For full disclosures of the study authors, visit cell.com.
