Preoperative treatment with the new drug vidutolimod and the PD-1 checkpoint inhibitor nivolumab led to tumor control in 55% of patients with stage 3 cutaneous melanoma, according to the results of a single-arm phase 2 clinical trial conducted by the University of Pittsburgh, UPMC Hillman Cancer Center, and the National Cancer Institute (NCI).
The findings, published in Cancer Cellsupport the development of vidutolimod for the treatment of cutaneous melanoma and provide important information that could advance research on this drug for use in other cancers.
This is the first and only clinical trial so far to test the innovative combination of nivolumab and the experimental drug vidutolimod in a neoadjuvant setting. It is exciting that we saw a 55% response rate, which is on par with currently approved immunotherapy combinations.”
Diwakar Davar, MD, lead author, associate professor, Pitt School of Medicine and UPMC Hillman
Vidutolimod, which has not yet been approved by the US Food and Drug Administration (FDA), targets the pattern recognition receptor TLR9, which is a protein that plays a critical role in initiating innate immune responses to foreign threats. TLR9-targeting agents are often included in drugs and vaccines because of their immune-enhancing effects, but less is known about how they work in combination with other cancer therapies.
For this phase 2 clinical trial, 31 patients with high-risk stage 3 resectable melanoma received seven injections of vidutolimod into their tumors and three rounds of intravenous nivolumab before surgery. After surgery, they continued to take both drugs every four weeks for a year.
After preoperative treatment, 55% of patients responded so well that less than 10% of viable cancer cells remained in the surgical specimen, which previous research has shown is a good predictor of long-term survival in melanoma patients. The remaining 45% of patients had either a partial (10-50% viable tumor) or no response (>50% viable tumor).
In patients with the highest response rate to combination therapy, the recurrence-free survival rate and metastasis-free survival rate were 88% and 94%, respectively.
When the researchers compared tumors and blood from patients who were high responders with those who were also non-responders, they found that plasmacytoid dendritic cells (pDC) and myeloid cells were enriched in the former compared to the latter. pDCs increase 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 enhance cancer immunotherapy. Neither pDCs nor myeloid cells are typically enriched in patients treated with nivolumab alone, so these observations suggest that vidutolimod stimulates antitumor immunity in a unique manner.
In experiments led by Amanda Paulovich, MD, of Fred Hutch Cancer Center and conducted as part of the Clinical Proteomic Tumor Analysis Consortium, researchers used a technique called mass spectrometry to show that most patients treated with vidutolimod and nivolumab had higher key levels. immune-related proteins, suggesting that unique signatures of TLR9 activation underlie drug activity.
“For any drug, it’s important to be able to measure proteins or markers that show whether a drug is working or not, which is known as a pharmacodynamic response,” Davar said. “It’s like when you put gas in the car, the gas gauge goes up to indicate you have a full tank. Before this work, we didn’t have a pharmacodynamic parameter for TLR9 agonists and other innate agonists, so identifying a protein associated with administration of TLR9 was a key finding.”
The research team also analyzed the patients’ gut microbiome. Specifically, 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 several other studies, including that of Davar and colleagues Hassane Zarour. MD, professor at Pitt School of Medicine and UPMC Hillman, and Giorgio Trinchieri, MD, head of the Laboratory of Integrative Cancer Immunology at the National Cancer Institute.
“Our data suggest that the mechanisms by which the gut microbiome modulates responses to cancer immunotherapy may differ depending on the specific treatment,” said Zarour. “Such new findings highlight the complexity and context-dependence of the effects of the gut microbiome on cancer immunotherapy and have led to ongoing studies to confirm this observation.”
Other authors in the study are cited in Cancer Cell manuscript.
Checkmate Pharmaceuticals (now owned by Regeneron Pharmaceuticals Inc.) provided funding for the clinical trial. This research was supported by the National Institutes of Health (R01 CA257265, P50 CA254865, R01 CA222203, U01CA268806, and U01CA271407), the Melanoma Research Foundation Breakthrough Consortium Team AFF Challenge Science Award.
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Journal Reference:
Davar, D., et al. (2024). Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial. Cancer Cell. doi.org/10.1016/j.ccell.2024.10.007.
