Combination therapy shows promising results in the treatment of stage 3 melanoma

According to a single-arm phase 2 clinical trial conducted by the University of Pittsburgh, UPMC Hillman Cancer Center and National Cancer Institute (NCI).

Results published in Cancer Cellsupport the development of vidutolimod for the treatment of cutaneous melanoma and provide critical insights that could advance research into this drug for utilize in the treatment of other cancers.

This is the first and only clinical trial to date testing the novel combination of nivolumab and the experimental drug vidutolimod in neoadjuvant treatment. “It is stimulating that we saw a response rate of 55%, which is comparable to currently approved immunotherapy combinations.”

Diwakar Davar, MD, lead author, associate professor at Pitt School of Medicine and UPMC Hillman

Vidutolimod, which has not yet been approved by the US Food and Drug Administration (FDA), acts on the pattern recognition receptor TLR9, a protein that plays a key role in initiating the innate immune response to foreign threats. TLR9-targeting agents are often incorporated into drugs and vaccines for their immune-enhancing effects, but less is known about their effects in combination with other cancer therapies.

In this phase II clinical trial, 31 patients with resectable, high-risk stage 3 melanoma received seven intratumoral injections of vidutolimod and three rounds of intravenous nivolumab preoperatively. After surgery, they continued to receive both drugs every four weeks for a year.

After preoperative treatment, 55% of patients responded so well that less than 10% of viable tumor cells remained in the surgical specimen, which previous studies have shown to be a good predictor of long-term survival for melanoma patients. The remaining 45% of patients had a partial response (10–50% viable tumor) or no response (>50% viable tumor).

In patients with the highest response rate to combination therapy, the two-year recurrence-free and metastasis-free survival rates were 88% and 94%, respectively.

When the researchers compared the tumors and blood of patients who responded to the treatment with high levels of response to patients who also did not respond, they found that plasmacytoid dendritic cells (pDC) and myeloid cells were richer in the former compared with the latter. pDCs boost the ability of T cells to eliminate tumors. Myeloid cells can suppress the immune response in tumors but can be targeted by many agents, including TLR agonists, to enhance cancer immunotherapy. Neither pDC nor myeloid cells are typically enriched in patients treated with nivolumab alone, so these observations suggest that vidutolimod uniquely stimulates antitumor immunity.

In experiments led by Amanda Paulovich of the Fred Hutch Cancer Center and conducted as part of the NCI Clinical Proteomic Tumor Analysis Consortium, researchers used a technique called mass spectrometry to show that most patients treated with vidutolimod and nivolumab had higher levels of key immune-related proteins, which suggests that unique TLR9 activation signatures underlie drug activity.

“For any drug, it is critical to be able to measure proteins or markers that indicate whether the drug is working or not, which is called the pharmacodynamic response,” Davar said. “It’s like when you put fuel in your car, the gas meter goes up to indicate that the tank is full. Before starting this work, we did not have a pharmacodynamic parameter for TLR9 and other innate agonists, so we identified the protein signature associated with the key finding was the administration of TLR9.”

The research team also analyzed the patients’ gut microbiome. Notably, patients whose tumors shrank the most had higher levels of Gram-negative bacteria, bacteria that are not typically associated with response to anti-PD1 therapy, according to multiple other studies, including one by Davar and co-author Hassane Zarour. M.D., professor at Pitt School of Medicine and UPMC Hillman, and Giorgio Trinchieri, M.D., chief of the Laboratory of Integrative Cancer Immunology at the National Cancer Institute.

“Our data suggest that the mechanisms by which the gut microbiome modulates the response to cancer immunotherapy may vary depending on the specific therapy,” Zarour said. “Such novel findings highlight the complexity and context-dependent influence of the gut microbiome on cancer immunotherapy and have prompted ongoing research to confirm this observation.”

Other authors of the study are listed in Cancer Cell manuscript.

Checkmate Pharmaceuticals (now owned by Regeneron Pharmaceuticals Inc.) provided financial support for the clinical trial. This research was supported by the National Institutes of Health (R01 CA257265, P50 CA254865, R01 CA222203, U01CA268806, and U01CA271407), a Melanoma Research Foundation Breakthrough Consortium Research Award, and a Visium Spatial FFPE Challenge Award.