Presurgical treatment with the novel drug vidutolimod and the PD-1 checkpoint inhibitor nivolumab may improve outcomes in patients with stage III cutaneous melanoma, according to a recent study published by Davar et al in Cancer Cell. The findings supported the development of vidutolimod for treating cutaneous melanoma and provided insights that may advance research on this drug for use in other cancer types.
Background
Vidutolimod—not yet approved by the U.S. Food and Drug Administration (FDA)—is capable of targeting 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 because of their immune-augmenting effects; however, little is known about how they work in combination with other cancer therapies.
Study Methods and Results
In the single-arm phase II clinical trial, researchers assigned 31 patients with high-risk, resectable stage III cutaneous 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.
Following presurgical therapy, the researchers found that treatment with the immunotherapy combination resulted in tumor control in 55% of the patients. These patients had less than 10% of viable tumor cells remaining—which previous research has shown to be a good predictor of long-term survival in this patient population. The other 45% of the patients had either partial (10%–50% viable tumor) or no response (> 50% viable tumor). In the patients with the greatest responses to the combination therapy, the 2-year recurrence-free survival and metastasis-free survival rates were 88% and 94%, respectively.
After comparing tumors and blood from the highest responding patients with those who didn’t respond as well, the researchers found that plasmacytoid dendritic cells and myeloid cells were enriched in the former compared with the latter. 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 such as TLR agonists to augment cancer immunotherapy. Neither plasmacytoid dendritic cells nor myeloid cells are typically enriched in patients treated with nivolumab alone, so these observations revealed that vidutolimod stimulated antitumor immunity in a unique way.
The researchers used a technique called mass spectrometry to show that most of the patients treated with vidutolimod and nivolumab had higher levels of key immune-related proteins, signifying that unique signatures of TLR9 activation may underlie the drugs’ activity. In addition, the researchers analyzed the gut microbiome of the patients. Of note, the patients whose tumors shrank the most had higher levels of Gram-negative bacteria, bacteria that are not usually 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. It’s exciting that we saw a response rate of 55%, which is on par with currently approved immunotherapy combinations,” highlighted lead study author Diwakar Davar, MD, Associate Professor at the University of Pittsburgh School of Medicine and the UPMC Hillman Cancer Center. “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. 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 emphasized.
“Our data suggest that the mechanisms by which the gut microbiome modulates responses to cancer immunotherapy may differ depending on the specific therapy,” underscored senior study author Hassane Zarour, MD, Professor at the University of Pittsburgh School of Medicine and the 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 provided by Checkmate Pharmaceuticals and supported by 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.
