Fecal Transplant May Resolve Immunotherapy-Related Colitis

Liam Davenport

November 14, 2018

For cancer patients who develop colitis as a result of immunotherapy, symptoms may resolve through fecal microbiota transplantation (FMT), preliminary findings suggest.

US researchers report success with this approach in two patients in an article published online November 12 in Nature Medicine.

The two patients had both developed colitis in association with the use of immune checkpoint inhibitors (ICIs). Colitis is a serious adverse event that can occur in up to 40% of patients who undergo treatment with these therapies.

One patient had received a combination of an anti–programmed cell death ligand–1 antibody together with an anticytotoxic T-lymphocyte–associated antigen–4 (CTLA-4) antibody. The other had been treated with the anti-CTLA-4 drug ipilimumab (Yervoy, Bristol-Myers Squibb).

In both cases, FMT led to complete resolution of the ICI-related colitis. Significant improvements were evidenced on endoscopic evaluation and were accompanied by ongoing changes in the gut microbiota.

"The resolution of colitis in these patients can be confirmed clinically and endoscopically after FMT treatment," commented lead author Yinghong Wang, MD, PhD, assistant professor of gastroenterology, hepatology, and nutrition, the University of Texas MD Anderson Cancer Center, Houston.

"Based on these results, this should be evaluated even as a first-line therapy for ICI-associated colitis because it's safe, quick, and the effect is durable &mdash from one treatment," she added.

The group has performed FMT on other patients, with similar results. These cases were not included in the case series because the final microbiome analysis for these cases was not yet available, Wang told Medscape Medical News.

"It seems like this pattern has been pretty consistent among the cases," she said, adding, "There is a plan that we are going to do a clinical trial as the next step."

ICI-associated colitis is routinely managed with immunosuppressive therapy, including corticosteroids and/or tumor necrosis factor–α (TNF-α) inhibitors, which are themselves associated with significant adverse events.

Another approach is to stop the immunotherapy. "If the patient is a good responder to immunotherapy, that means you've taken their effective treatment away," Wang commented. "We have a limited amount of time to fix the problem so they can resume ICI treatment."

Novel Treatment Approach

FMT has emerged in recent years as a novel treatment approach for Clostridium difficile–associated colitis and inflammatory bowel disease.

For their study, Wang and colleagues used the approach in the treatment of ICI-related colitis on a compassionate-use basis.

The two patients described in the article underwent stool transplants from healthy donors between June 2017 and January 2018. The tranplants were delivered to the colon via colonoscopy.

The first patient was a 50-year-old women with high-grade metastatic urothelial carcinoma that was refractory to standard chemotherapy. The patient was enrolled in the CheckMate-032 trial of CTLA-4 and programmed cell death protein 1 blockade.

During a period of 2 weeks, the colitis completely resolved. The patient was weaned off steroids in 7 days.

The second patient was a 78-year-old man with prostate cancer that was refractory to chemotherapy and hormonal therapy. The patient was given two doses of ipilimumab as part of another clinical trial.

After FMT, he experienced partial improvement of his gastrointestinal symptoms but was found to have persistent ulcers on follow-up colonoscopy. He also experienced recurrent abdominal pain.

The patient received a second FMT, which led to a complete resolution of the ICI-associated colitis.

At baseline, both patients had significant mucosal inflammation and ulceration, which had not improved markedly after treatment with systemic corticosteroids and anti-TNF-α and anti-integrin drugs.

For both patients, marked improvement was seen on endoscopy after FMT. There was reduction of inflammation, a reduction in the numbers of inflammatory cells, and resolution of ulcerations.

The researchers note that the patients' gut microbiomes resembled their donors' most closely immediately after FMT, but this resemblence diminished over time. Some bacteria remained distinct from the pretreatment population.

In addition, some new bacterial species were identified in the microbiome that were not present in the pretreatment samples. Several of those species are protective against or reduce inflammation.

"Together, these cases provide provocative and novel evidence that modulation of the gut microbiome via FMT can be associated with significant and rapid improvement of refractory ICI-associated colitis with early insights into potential mechanisms," the team write.

"However, significant limitations exist with this very small cohort and additional studies are needed to assess the utility of this approach as well as to provide further mechanistic insight," they add.

The study was funded by the Andrew Sabin Family Fellows Program, MD Anderson Cancer Center's Melanoma Moon Shot Program, the American Association for Cancer Research Stand Up to Cancer, the National Institutes of Health, and the Cancer Prevention and Research Institute of Texas. Dr Wang has disclosed no relevant financial relationships. Coauthors' relevant financial relationships are listed in the original article.

Nat Med. Published online November 12, 2018. Abstract

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