A fecal transplant could advance immunotherapy to treat melanoma

IMMunotherapy, a type of intervention that releases the body’s immune cells to better fight cancer, has been a lifesaver for some patients. But it doesn’t work for everyone, and researchers have been trying to figure out why. The results of two small studies now show that in some patients with melanoma who initially did not respond to one type of immunotherapy, the tumors may shrink when the drugs are paired with a fecal transplant from a donor who had improvement after the same cancer treatment. The results complement evidence that the bacterial mixture in the gut known as the microbiome affects the effectiveness of immunotherapy.

The studies “were both really exciting evidence of the principle of potentially using FMT [fecal microbiota transplantation] Jennifer McQuade of the MD Anderson Cancer Center, who studies factors that influence the success of immunotherapy for melanoma and was not involved in either study. Although both Phase 1 studies were small, the results support a step towards larger studies.

Both studies were published together on February 5th in sciencealthough one appeared on the magazine’s website in December. One of the studies was conducted at the Sheba Medical Center in Israel and includes the results of the first 10 patients enrolled. The other group included 15 patients and was located at the National Institutes of Health (NIH) and the University of Pittsburgh Medical Center (UPMC). All 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 benefited to some extent from the therapy. Donors in the Israeli study fully responded to therapy, which meant their cancers were undetectable, while donors in the NIH / UPMC study were a mix of full responders and patients whose tumors had shrunk but not gone . Phase 1 studies primarily evaluate safety and the authors did not find any major safety issues with FMT treatment. None of the studies included a control group.

Previous studies have shown a link between certain types of bacteria in patients’ intestines and the effectiveness of immunotherapy, and animal studies have suggested a causal role. However, these are the first clinical studies to suggest that changing the microbiome could affect the response to immunotherapy in humans. Faecal transplants are already a recognized therapy for a so-called gastrointestinal disease C. difficile Colitis and have been tested for other conditions that involve a disorder of the gut microbiome. Even so, it was initially difficult to convince colleagues to refer patients to his study, says Gal Markel, co-author of the Israeli study now at Rabin Medical Center and Tel Aviv University. “It sounds a bit strange, it sounds very low-tech. . . with a very crazy reason, ”he explains.

See “Does the Microbiome Help the Body Fight Cancer?”

That changed after the third patient in the study showed notable improvement. “We saw the reaction right under our eyes,” he says, as metastatic tumors on the patient’s skin shrunk. Overall, one of the first 10 patients who participated in the study went into remission and two others showed partial reactions, report Markel and his colleagues. Without FMT, it’s not uncommon for patients to have a delayed response to immunotherapy, but it’s rare, says McQuade. When patients with metastatic melanoma do not respond to immunotherapy, their disease usually progresses unless their doctors find another treatment that works. Markel has now co-founded a company, Ella Therapeutics, which took over the study from Sheba Medical Center and is adding another 41 patients, he says.

In the NIH / UPMC study, six of the 15 patients whose results were reported had complete or partial responses to treatment.

It is to be expected that not all patients will benefit from it, says McQuade. One question that needs to be addressed in larger studies is, “How can we better choose which patients would benefit from FMT? . . . Patients do not respond to immunotherapy for various reasons. ”

See “How the Microbiome Affects Drug Action”

The researchers plan to find out which types of bacteria are important in further fecal transplant trials. This question has not been answered by previous observational studies that have produced mixed results. “The field was kind of confusing; We’re still working hard to really understand what types of bacteria are important and what their mechanisms are, ”says Giorgio Trinchieri of the NIH Center for Cancer Research, who co-authored the NIH / UPMC study.

Ultimately, researchers said The scientistThis type of knowledge could lead to other therapies that offer the potential benefits of fecal transplantation without the need for a donor stool. In addition to its “ick” factor, fecal transplants must be screened for pathogens prior to transplantation (which can be done with either a pill or colonoscopy). Generally, only academic medical centers perform the procedure. As in C. diffA fecal transplant “is always a good way to start as a proof of concept, but I think ultimately people want – I would think – find more specific ways to manipulate the microbiota,” for example through probiotics, says Andrew Y. Koh who studied the impact 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 part of the Israeli study. In addition to the scientific implications, he says, “To see how your patients react. . . From a personal point of view, it’s very powerful. “

EN Baruch et al., “Fecal Microbiota Transplantation Promotes Response in Patients with Immunotherapy-Refractory Melanoma”. science371, 602-609, 2021.

D. Davar et al., “Fecal Microbiota Transplantation Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients” science371, 595-602, 2021.

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