Immunotherapy, a type of intervention that unleashes the body’s own immune cells to better fight cancer, has been a lifesaver for some patients. But it doesn’t work for all, and researchers have been trying to figure out why that is. Now, results from a pair of small trials indicate that some patients with melanoma who don’t initially show a response to one type of immunotherapy can see their tumors shrink if the drugs are paired with a fecal transplant from a donor who had improvement after the same cancer treatment. The findings add to evidence suggesting that the mix of bacteria in the gut, known as the microbiome, influences immunotherapy’s effectiveness.
The studies “were both really exciting proof of principle to potentially being able to use FMT [fecal microbiota transplantation] to augment response to immunotherapy cancer patients,” says MD Anderson Cancer Center’s Jennifer McQuade, who studies factors influencing the success of immunotherapy in melanoma and was not involved in either study. While both Phase 1 trials were small, she adds, the results support a move ahead to larger studies.
Both studies were published together on February 5 in Science, although one appeared on the journal’s site in December. One of the trials was based at Sheba Medical Center in Israel and includes the results of the first 10 patients enrolled; the other included 15 patients and was based at the National Institutes of Health (NIH) and the University of Pittsburgh Medical Center (UPMC). All of the participants were melanoma patients who had not responded to a type of immunotherapy known as anti-PD-1, and therefore received fecal transplants from patients who had benefitted from the therapy to some degree. Donors in the Israeli trial had complete responses to therapy, meaning their cancers were no longer detectable, while donors in the NIH/UPMC trial were a mix of complete responders and patients whose tumors had shrunk but not disappeared. Phase 1 trials principally assess safety, and the authors did not find any major safety issues with FMT treatment. Neither study included a control group.
Past studies have shown an association between certain types of bacteria in the guts of patients and whether immunotherapy is effective, and animal studies have pointed to a causal role, but these are the first clinical trials to suggest that changing the microbiome could affect immunotherapy response in humans. Fecal transplants are already an accepted therapy for a gastrointestinal condition called C. difficile colitis and have been tested for other conditions that involve disruption of the gut microbiome. Nevertheless, it was initially difficult to persuade colleagues to refer patients to his trial, says Gal Markel, a coauthor on the Israeli study who is now at Rabin Medical Center and Tel Aviv University. “It sounds a bit strange, it sounds very low tech . . . with a very crazy rationale,” he explains.
That changed after the third patient in the trial had a striking improvement. “We saw the response right under our eyes,” he says, as metastatic tumors on the patient’s skin shrank. Overall, of the first 10 patients enrolled in the trial, one went into remission, and two others showed partial responses, Markel and his colleagues report. Without FMT, it’s not unheard of for patients to have a delayed response to immunotherapy, but it’s rare, says McQuade; typically, if metastatic melanoma patients don’t respond to immunotherapy, their disease continues to progress unless their doctors find a different treatment that’s successful. Markel has now cofounded a company, Ella Therapeutics, that has taken over the trial from Sheba Medical Center and is adding an additional 41 patients, he says.
In the NIH/UPMC study, six of the 15 patients whose results are reported showed a full or partial response to the treatment.
It’s to be expected that not all patients will benefit, says McQuade. One question to address in larger studies, she adds, is, “how do we get better at actually selecting which patients would benefit from FMT? . . . Patients fail to respond to immunotherapy for a variety of reasons.”
The researchers plan to tease out in further fecal transplant trials which bacterial species are important, a question unanswered by previous observational studies that reached different results. “The field has been sort of confusing; we’re still working a lot on that to try to really understand which bacterial species are important, and what is the mechanism,” says Giorgio Trinchieri of NIH’s Center for Cancer Research who coauthored the NIH/UPMC study.
Ultimately, researchers told The Scientist, this type of knowledge could lead to other therapies that confer the potential benefits of a fecal transplant without the need for donor stool. In addition to its “ick” factor, fecal transplants need to be screened for pathogens before being transplanted (which can take place either with a pill or a colonoscopy), and generally, only academic medical centers carry out the procedure. As with C. diff, fecal transplantation “is always a good way to start out as proof of concept, but I think ultimately, people would like to—I would think—find more specific ways to manipulate the microbiota,” such as through probiotics, says Andrew Y. Koh, who studies the influence of the microbiome on cancer at the University of Texas Southwestern Medical Center and was not involved in either study.
Markel says he feels privileged to have been a part of the Israeli study. In addition to its scientific implications, he says, “to see your patients responding . . . from personal perspective, it is very powerful.”
E.N. Baruch et al., “Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients,” Science, 371:602–609, 2021.
D. Davar et al., “Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients,” Science, 371:595–602, 2021.