Could fecal transplants improve melanoma treatment?

• Combining fecal transplants with immune checkpoint inhibitors such as pembrolizumab or nivolumab showed the procedure was safe in people with advanced melanoma, according to a phase 1 clinical trial.
• Of the study participants, 65% responded positively to immunotherapy treatment.
• Positive responders also showed an increase in beneficial bacteria and a decrease in harmful bacteria in their gut microbiome following the fecal transplant.
• The researchers plan to conduct larger phase 2 trials and explore using fecal transplants in hard-to-treat cancers like pancreatic cancer.

In recent years, a type of treatment called immunotherapy has been helping many people with cancer by harnessing their immune systems to recognize and destroy cancer cells.

Some drugs used in immunotherapy, like pembrolizumab (Keytruda) and nivolumab (Opdivo), work by stopping the mechanism that allows cancer cells to hide from the immune system.

These ‘anti-programmed death (PD-1) drugs’ or ‘immune checkpoint inhibitors’ are effective in treating nearly 50% of people with melanoma (a type of skin cancer).

Recently, scientists tested combining immunotherapy with fecal microbiota transplants in patients with advanced melanoma to see whether this could improve their response.

Not only was this combination safe, but most patients also saw a positive response to the treatment, with some achieving complete remission.

The study is published in Nature Medicine.

The phase 1 trial

In the phase 1 MIMic trial, the researchers combined fecal transplants with the approved drugs pembrolizumab or nivolumab, which are already used as standard treatment for advanced melanoma.

The goal of the clinical trial was to assess if it is safe to combine these two treatments in people with melanoma. The effects of fecal transplants on the immune system and the gut microbiome were also assessed as secondary objectives.

Healthy donors were carefully selected according to Health Canada-approved procedure. The fecal samples from healthy donors were then manufactured into capsules.

The trial recruited 20 people with advanced melanoma from three study centers: Lawson Health Research Institute, the Centre Hospitalier de l’Université de Montréal (CRCHUM) and the Jewish General Hospital (JGH).

Each study participant received capsules that contained 80-100mg of fecal transplant from one healthy volunteer donor. The fecal transplants were delivered by oral capsules at least one week before treatment with approved immunotherapy drugs (either pembrolizumab or nivolumab).

Is fecal transplantation plus immunotherapy safe?

All 20 patients were able to complete the fecal transplantation procedure.

Eight patients (40%) experienced mild to moderate side effects related to fecal transplantation, including diarrhea, flatulence, and abdominal discomfort, but no serious side effects were observed before starting immunotherapy, and no infections were transmitted through fecal transplantation.

Of the patients, 17 people (85%) experienced immune-related side effects, most of which (70%) occurred within the first three months after starting immunotherapy. Of these, five study participants (25%) had severe immune-related side effects, including arthritis (n = 2), fatigue (n = 1), pneumonitis (n = 1), and nephritis (n = 1), which led to treatment discontinuation.

The researchers did not observe any previously unreported side effects of fecal transplantation or immunotherapy.

Did combination therapy improve outcomes?

Among the study participants, 65% (13 out of 20) had a positive response to the treatment, with four of them (20%) experiencing complete remission.

Analysis of their gut microbiome showed that all patients developed strains from the donor’s bacteria, but this similarity only increased over time in the patients who responded well to the treatment. Responders had an increase in beneficial bacteria and a decrease in harmful bacteria following fecal transplantation.

The researchers also conducted tests on mice that confirmed the positive effect of healthy donor feces in enhancing the efficacy of immunotherapy.

What is fecal microbial transplantation?

Fecal microbial transplantation (FMT), or fecal transplantation for short, is a medical procedure in which stool (feces) from a healthy person (the ‘donor’) is collected and transferred into the intestines of the recipient.

The purpose of this procedure is to introduce healthy bacteria into the recipient’s intestines, which can help treat medical conditions related to disturbances in gut bacteria.

Fecal transplantation has been used successfully to treat persistent infections with Clostridium difficile.

A fecal transplant is typically performed through a colonoscopy but is sometimes given as a capsule.

Linking the gut and the immune system

So, why is it that not everyone responds to immune checkpoint inhibitors?

Recent evidence suggests that the microorganisms living in the gut may affect how well the drugs work. People who respond to immune checkpoint inhibitors have a unique and healthy gut microbiome (or ‘group of microorganisms in their gut’).

After observing the potential link between the gut microbiome and response to immune checkpoint inhibitors, Saman Maleki, Ph.D., assistant professor of oncology, pathology and laboratory medicine, and medical biophysics at Western University, and scientist at London Regional Cancer Program and Lawson Health Research Institute, and one of the study authors, reasoned that changing a person’s gut microbiome to make it more diverse and healthy may improve their response to immunotherapy.

One way of changing the gut microbiome is through fecal microbial transplantation.

Will fecal transplants be a part of melanoma treatment?

Dr. John Lenehan, medical oncologist at London Regional Cancer Program, associate scientist at Lawson Health Research Institute, associate professor of oncology and family medicine at Western University, and principal study investigator, told Medical News Today the most important finding in this study, for him, was that “none of the patients were harmed by the experimental treatment.”

Observational and pre-clinical data had shown fecal transplants to be helpful, “but what happens in mice does not always translate to patients,” he said. Indeed, Dr. Lenehan noted that “more recent studies using similar therapies have shown harm, with patients having a worse response.”

He explained that these other studies performed fecal transplantation differently from the MIMic trial.

“There are many variables such as bowel preparation, how many FMTs need to be done, how much stool is needed, who should the donors be? We did not know if our method would be safe or effective. Fortunately, it seems that it was both!” he said.

Hannah Wardill, Ph.D., research fellow at the Hospital Research Foundation Group and leader of the Supportive Oncology Research Group at the University of Adelaide, who was not involved in this study, believes that this combination therapy approach has the potential to become a successful treatment.

“FMT is a reasonably accessible intervention, and this study shows it is safe and likely effective and improving immunotherapy response,” she told MNT.

By enhancing response rate in people who would otherwise be unresponsive to immunotherapy, the combination of fecal transplants and immunotherapy means that “more people will benefit from immunotherapy,” Dr. Wardill explained.

Next trials in Canada

In his comments to MNT, Dr. Maleki expressed his eagerness “to expand our studies to other disease settings, such as pancreatic cancer and breast cancer. Currently, trials on both are being organized.

“We are also working with the Canadian Cancer Trials Group to organize a national randomized trial of FMT plus immunotherapy in melanoma patients in Canada, which can open the path for a registration trial to change the standard of care in melanoma,” Dr. Maleki said.

When asked about what future studies should focus on, Dr. Wardill replied:

“One of the most fascinating things for immunotherapy is that often people who respond well have a very high side effect burden. It seems the same mechanisms that dictate response also dictate toxicity. So what we need to now think about is how we can enhance response in refractory patients without increasing their side effect risk. This definitely needs to be a focus of studies moving forward.”

Dr. Wardill added that “immunotherapy is often used in combination with chemotherapy, and so we need to know how to use FMT in this more complex clinical setting.”

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