ATHENS, Greece — Two strategies under investigation suggest that manipulating the gut microbiome could improve the effectiveness of immunotherapy in patients with melanoma, according to new research presented at the 11th World Congress of Melanoma (WCM) and 21st EADO Congress 2025.
The first strategy involves designing a live biotherapeutic product that mimics the gut bacterial composition of stool from a super donor — in this case, a cancer patient who had achieved a complete response to immunotherapy. This stool could then be administered using this product to nonresponders to help them overcome resistance to treatment.
The second strategy involves exploring whether a high-fiber diet in patients with melanoma can alter the gut microbiome and enhance patients’ responses to immunotherapy.
“By strategically reprogramming the gut microbiota, we can potentially transform nonresponders into responders, amplifying the clinical benefit of immunotherapies that would otherwise fail to harness the full potential of the immune system against cancer,” Nadim Ajami, PhD, executive director of scientific research at MD Anderson Cancer Center at The University of Texas, Houston, told Medscape Medical News.
The core idea is that the balance of bacteria in the gut can influence whether T cells are activated or suppressed in the tumor microenvironment. Optimizing these T cell responses may help patients overcome resistance or respond better to immunotherapy, Ajami explained.
At the meeting, Ajami reported insights from recent preclinical and clinical work, highlighting the early promise of this research.
The Power of a Super Donor Microbiome
Early clinical trials have suggested that in patients with immunotherapy-refractory metastatic melanoma, fecal microbiota transplantation (FMT) may improve patients’ response to therapy. An analysis, published in Science in 2021, found that, among 15 patients in a phase 1 trial, six had a response to pembrolizumab following fecal transplant — one complete response, two partial responses, and three had stable disease for a year.
“While FMT studies gave us critical insights, they’re inherently challenging to standardize and nearly impossible to scale clinically,” said Ajami. “By manufacturing the ‘active components’ of FMT (bacteria) into a defined live biotherapeutic, we gain enormous advantages.”
Ajami’s team, alongside collaborators at Kanvas Bio, have developed a live biotherapeutic agent composed of a bacterial consortium that aims to optimize the gut microbiome of patients with melanoma.
The specific bacterial consortium was derived from the gut microbiome of a super donor. Super donors are extremely rare, Ajami said.
This donor — a colorectal cancer survivor who had a complete response to immunotherapy — was identified through an ongoing FMT trial at MD Anderson Cancer Center.
The team characterized the super donor’s microbiome using a new imaging tool — a high-phylogenetic-resolution spatial mapping platform — that enables comprehensive profiling of microbial communities. The researchers were then able to develop successive formulations of a live biotherapeutic product to replicate the beneficial bacterial effects from the super donor.
“Essentially, we’re transforming a donor-dependent, variable procedure into a standardized therapeutic that can be reliably manufactured, precisely dosed, and integrated into clinical practice,” said Ajami.
He highlighted preclinical data demonstrating that the biotherapeutic achieved the same antitumor response as the original super donor FMT material in a mouse model of immunotherapy-refractory melanoma.
Ideally, in patients, the biotherapeutic product can be delivered orally via pill form that would only release contents in the large intestine, though it could also be delivered via a colonoscopy, Ajami explained. The mode of delivery and frequency and how those affect engraftment and clinical outcome are still open questions, he noted.
Ajami said the work is with the US Food and Drug Administration for a pre–Investigational New Drug consultation.
Dietary Fiber to Enhance Response
Ajami’s team, in collaboration with Jennifer McQuade, MD; Carrie Daniel-MacDougall, PhD, MPH; and Jennifer Wargo, MD; all from MD Anderson, has also explored whether a dietary intervention can improve patients’ response to immunotherapy.
An initial phase 1 trial established the safety and feasibility of providing patients with a fiber-enhanced diet for 6-10 weeks. The subsequent phase 2 is a double-masked, randomized, controlled trial that enrolled 45 patients with melanoma starting treatment with first-line immunotherapy. The intervention involved increasing the intake of dietary fiber over 10 weeks to 50 g/d in the high-fiber group, with patients in the low-fiber group consuming only 20 g/d.
The diets in both groups were extremely healthy and included foods that we know contain soluble and insoluble fiber, like apples, chia seeds, beans, and broccoli, Ajami explained.
Among the 20 evaluable patients so far, 77% (10 of 13) in the high-fiber group responded to immunotherapy compared with 29% (2 of 7) in the control group.
Although the trial is limited by its small patient population, Ajami said the preliminary results are encouraging.
Thomas Gajewski, MD, PhD, a medical oncologist at the University of Chicago, Chicago, said that no harm can come from prescribing high-fiber diets to patients, though Andrew Birnie, MD, a consultant dermatologist at the Kent and Canterbury and William Harvey Hospitals, argued that such a high-fiber diet might not be easily implemented.
Ajami acknowledged that fiber consumption plummeted immediately after the controlled feeding period ended in both trial phases.
However, “none of these studies were intended for behavior modulation,” Ajami said. “These studies were intended to [begin to] understand the effects of a high-fiber diet on response to immunotherapy.”
Ajami reported research collaboration and licensing agreements with Kanvas Bioscience and SNIPR BIOME. He was named Inventor in patent applications related to the detection of microbes and microbiome modulation.
Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, The Guardian, MIT Technology Review, and others.