Stool Transplants May Boost Immunotherapy Success in Melanoma

Jim Kling

November 29, 2022

In advanced and metastatic melanoma patients, fecal microbiota transplant (FMT) from healthy donors in advance of anti–PD-1 immunotherapy led to a 75% clinical benefit rate, defined as complete response, partial response, or stable disease that lasted 6 months or longer. The results come from a small, single arm phase 1 study whose primary endpoint was safety.

"We know that the gut microbiome has shown the ability to affect the systemic antitumor immunity by affecting the CD8+ T cells and CD4+ T cells, and these are the cells that are ultimately important for the function of checkpoint inhibitors. There is now clinical evidence that has shown that changing patient microbiota via fecal microbiota transplantation using stool from previous responder patients has the capacity to sensitize immunotherapy refractory melanomas to anti–PD-1 therapy, (with) about 30% response in this setting," said Saman Maleki, PhD, during his presentation of the results at the Society for Immunotherapy of Cancer's 37th Annual Meeting. He also noted that broad-spectrum antibiotics have been shown to negatively influence responses to immunotherapy.

Rather than using stool from donors who responded to immunotherapy, the researchers chose instead to use stool from healthy donors.

The study included 20 patients with advanced melanoma who had not been treated with anti–PD-1 therapy. The median age was 75.5 years, 40% were female, and 75% had wild type BRAF. All patients underwent bowel prep and then received fecal transplants from healthy donors, followed by a 7-day engraftment period before initiating anti–PD-1 therapy in the form of nivolumab or pembrolizumab.

The primary endpoint of the study was safety, and no grade 3 or 4 toxicities were observed during the FMT, and safety signals associated with anti–PD-1 therapies were in line with previous experience.

Fifteen percent of patients had a complete response, 50% had a partial response, 15% had stable disease, and 20% had progressive disease. Seventy-five percent of patients had a complete response, partial response, or stable disease that lasted at least 6 months.

Analysis of the microbiomes showed much higher diversity in the donor microbiomes than in patients. "What was really interesting was that the success of engraftment and retention of the donor microbiome was really key in determining between responders and nonresponders. Responders had successful engraftment that lasted over time, and in nonresponders we did not see that," said Maleki, who is a cancer immunology researcher at the University of Western Ontario, London.

They also saw differences between responders and nonresponders in how their microbiome evolved over time. Responders had enrichment in Ruminococcus callidus and other bacteria, while nonresponders had enrichment in different bacteria, among them Catabacter hongkongensis, which has previously been implicated as negatively impacting anti–PD-1 responses, according to Maleki.

Microbiomes from healthy donors had greater diversity than the patients. Following FMT, patients' microbiomes increased regardless of clinical response to immunotherapy. However, the tendency for patients to trend toward and retain greater diversity over time was associated with treatment success. "What we saw that was key in patients' response to immunotherapy was the ability of the patients to retain the donor microbiome. All patients' microbiomes changed and shifted toward the donors' post FMT. However, only the responders were able to keep the donor microbiome over time, and the nonresponders' microbiomes reverted to the previous microbiome," Maleki said.

The researchers also conducted a mouse version of the clinical trial. They transplanted mice with the baseline fecal samples of a human responder and then exposed the animals to tumors. They then conducted a second FMT with stool from the human donor, and the animals then responded to anti–PD-1 therapy. The results further confirm "that the donor still has the capacity to drive response in this setting," Maleki said.

Maleki is a board member of IMV Inc.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....