Houston, Texas, USA : A case study of two patients with advanced cancer shows it might be possible to avoid a common and severe side effect of immunotherapy treatment.
Two cancer patients were successfully treated with fecal microbiota transplants (FMTs) for colitis caused by immunotherapy, according to a case report published today (November 12) in Nature Medicine. Both patients accepted donors’ gut microbiomes following the procedure and their symptoms cleared up within weeks.
For the first time, transplanting gut bacteria from healthy donors was used to successfully treat patients suffering from severe colitis caused by treatment with immune checkpoint inhibitors (ICIs). The study from The University of Texas MD Anderson Cancer Center, which includes two patients, suggests fecal microbiota transplantation (FMT) is worth investigating in clinical trials as a therapy for this common side effect of immunotherapy.
The research, led by Yinghong Wang, M.D., Ph.D., assistant professor of Gastroenterology, Hepatology & Nutrition and director of Medication Induced Colitis and Enteritis, was published today in Nature Medicine.
“The resolution of colitis in these patients can be confirmed clinically and endoscopically after FMT treatment,” said Wang. “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 – from one treatment.”
Immune checkpoint inhibitors, which release a block on the immune system to attack cancer, have been successful in providing durable responses for patients with several cancer types. However, these treatments are often associated with significant immune-related toxicities.
Colitis, inflammation of the colon, is the second most common side effect from ICIs, occurring in up to 40 percent of patients, explained Wang. When ICI-associated colitis is severe, guidelines require a patient to stop ICI treatment until the colitis is in remission.
“If the patient is a good responder to immunotherapy, that means you’ve taken their effective treatment away,” said Wang. “We have a limited amount of time to fix the problem so they can resume ICI treatment, but I feel that we’ve made great progress in this area.”
The researchers chose to investigate the potential for FMT as an alternative, compassionate-use therapy for patients suffering from refractory, or unresponsive, ICI-associated colitis. The two patients included in the study were treated at MD Anderson between June 2017 and January 2018.
FMT has shown promise in treating other types of gastrointestinal diseases, such as recurrent Clostridium difficile infection and inflammatory bowel disease (IBD), which shares many clinical and molecular characteristics with ICI-associated colitis. These conditions typically are treated with steroids and targeted immunosuppressive agents, which result in additional severe side effects and can counteract the effects of immunotherapy.
Both patients in the study had a complete resolution of their colitis following treatment with FMT. The first patient’s colitis resolved within two weeks following a single FMT treatment; the second patient experienced a partial recovery after the first treatment, followed by complete recovery after a second FMT. With endoscopic evaluation before and after treatment, both patients displayed significant improvements in inflammation and ulcerations, including a reduction of inflammatory immune cells.
Pre- and post-treatment stool analyses revealed patients’ gut microbiomes to be most similar to the donor immediately after treatment, with less resemblance to the donor over time. Still, post-treatment gut bacteria remained distinct from their own pre-treatment microbiome. Additionally, distinct new populations of bacterial species were evident in these patients following FMT compared to pre-treatment samples, including several species known to be protective or reduce inflammation.
The authors acknowledge significant limitations to this study based on the very small cohort, and they plan to pursue clinical trials to investigate the effectiveness of FMT in treating ICI-associated colitis as compared with standard immunosuppressive therapy. FMT continues to be offered to MD Anderson patients on a compassionate-use basis.
Previous MD Anderson research showed that bacteria in the gut influence patient response to ICI therapy, and other evidence suggests modifying the microbiome in mice can alter their response to immunotherapy. The current data further suggests there is the potential for many molecular studies to better understand the role of the microbiome in driving ICI-colitis and immunotherapy response more broadly.
The study was supported by the Andrew Sabin Family Fellowship Program; the American Association for Cancer Research – Stand Up to Cancer; the National Institutes of Health (CA219896-01A1, HL124112); the Cancer Prevention & Research Institute of Texas; and the Melanoma Moon Shot™, part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
“This is an exciting, small case series that shows the therapeutic potential of fecal microbiota transplant for a relatively common complication of immunotherapy treatment,” says Ami Bhatt, an oncologist who studies the role of microbes in cancer at Stanford University and who was not involved in this work. “This is the first time that a fecal transplant has been shown to be promising for a therapy-related complication.”
For Bhatt, this initial study is also important because it underscores the severe and often treatment-limiting side effects that can come with immunotherapy and that have implications for how cancer patients fare from these therapies.
Immune checkpoint inhibitor antibodies such as those that target cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) found on the surface of T cells help rev up the immune system to attack tumor cells. These checkpoint inhibitor antibodies are now approved by the US Food and Drug Administration to treat a range of advanced tumor types including melanoma, lung cancer, and kidney cancer. While typically prolonging patients’ lives, the therapies can also damage the immune system, causing colitis, or inflammation of the colon, skin rashes, and liver inflammation.
“With the increased use of checkpoint inhibitors to treat cancer patients, we have seen an increase in the number of patients that have gastrointestinal toxicity,” says study author Yinghong Wang, a gastroenterologist at the University of Texas MD Anderson Cancer Center in Houston. “And unfortunately, we still don’t have good quality data on how to manage some of these patients that have severe forms of this toxicity.”
Immunotherapy-treated cancer patients who develop colitis are initially treated with immunosuppressive steroids. If this doesn’t work, then doctors try additional nonsteroidal drugs that help to quell the immune system. About half of patients who develop colitis don’t respond to the initial steroid treatment, according to Wang. “We often have to stop the immunotherapy, and the immunosuppression may potentially counteract the checkpoint inhibitor activity,” she tells The Scientist.
Transferring stool microbes from healthy donors is now an established way to prevent and clear recurrent Clostridium difficile infections. Wang had previously performed many FMTs on patients with C. difficile infections and wanted to test FMTs as an alternative and potentially safe colitis treatment that did not suppress the immune system.
For the transplant, fecal matter is collected from a healthy donor, strained to collect the bacteria and other microbes, and delivered to the patient’s colon. Donors are screened to make sure they don’t have a history of health issues and the bacteria are assessed for any possible pathogens. Sometimes patients’ family members serve as the FMT donor.
“FMTs attempt to normalize the gut microbiota ecosystem in patients whose gut ecosystems have been disrupted by infection, antibiotics, or other reasons, no matter whether it’s cancer patients or those with bowel disorders,” says Alexander Khoruts, a gastroenterologist and immunologist at the University of Minnesota who performs fecal transplants and was not involved in the work.
Wang and her colleagues performed the FMTs on two immunotherapy patients who had severe colitis. Both already failed to respond to steroids and immunosuppressive antibodies for their gut inflammation. One patient had advanced metastatic urothelial carcinoma and was being treated for her cancer with a combination of anti-CTLA-4 and anti-PD-1 antibodies as part of a clinical trial. After the FMT, her symptoms resolved within two weeks, and the gut inflammation almost completely recovered in one month, confirmed by a colonoscopy.
The second patient had advanced prostate cancer and received an anti-CTLA-4 antibody therapy, also part of a clinical trial. This patient partly recovered from the colitis, but had remaining ulcers after the first FMT. So Wang’s group delivered another round of donor microbes and the colitis cleared up, also confirmed by colonoscopy.
In both patients, effector T cells within the colon decreased and regulatory T cells, which dampen the immune system, increased, a sign that the gut inflammation had subsided.
The team also collected the patients’ stool samples before and after the fecal transplants to analyze their microbiomes. Between the two patients, there was little overlap in the bacterial species detected prior to the transplants, but following the microbial transfers, both had an increase in gut microbes associated with a healthy colon. “I wouldn’t draw any strong conclusions from the microbiome data here because it’s from a limited number of patients,” says Bhatt.
What exactly constitutes a healthy microbiota still remains unclear. “There is a somewhat emerging standard approach for identifying a favorable gut microbiota, which is one from a healthy donor that has lots of diverse bacterial species,” says Thomas Gajewski, a cancer clinician and researcher at the University of Chicago who studies the role of the gut microbiota in modulating patients’ responses to immunotherapy and was not involved in the study. “But we don’t truly know the answer in any detail as to what the specific bacterial contents should be in donor fecal material to achieve beneficial effects.”
The MD Anderson team would like to now test the effectiveness of FMTs to treat colitis in patients receiving checkpoint inhibitor immunotherapy in a large clinical trial.
Citation : Y. Wang et al., “Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis,” Nature Medicine, doi.org/10.1038/s41591-018-0238-9, 2018.