Cancer Gets Pooped

Changing the microbiome helps some melanoma patients

Jamie Reittinger, a father of three in Tipp, Ohio, was living in the shadow of a deadly cancer when he ran out of treatment options in the fall of 2018. Three years before he had what initially looked like a wart under his thumbnail— it turned out to be melanoma.

Reittinger was referred to UPMC Hillman Cancer Center, where a multidisciplinary team of doctors recommended an amputation of half his thumb. Despite the radical surgery, the cancer resurfaced three years later—this time, it had spread to his lungs.

Melanoma is the deadliest form of skin cancer. Although timely treatment and surgery is curative in most cases, sometimes patients develop advanced melanoma.

Hassane Zarour with an orange backgroundIn the past decade, a new wave of immunotherapies has changed cancer care. These monoclonal antibodies have transformed many cancers, including melanoma. Yet only about 40% of melanoma patients respond, and Reittinger fell into a vexing majority of patients whose cancers fail to respond to these treatments.

“Cancer immunologists are really trying to improve upon current immunotherapies,” says Hassane Zarour, professor of medicine, immunology and dermatology at the University of Pittsburgh, who coleads the UPMC Hillman Cancer Center Melanoma Program. “We need to find ways for people with advanced cancers to respond to these treatments.”

Yet this is not a story of personal loss and tragedy. So far, for Reittinger and a few others in similarly dire straits, things have turned out well—remarkably so. What turned the tide for them is an unusual treatment involving other peoples’ poop—and researchers are barely past the starting line of a long race to figure out how and why it helped.

Diwakar Davar with blue background In the fall of 2018, Diwakar Davar, a hematologist/oncologist and assistant professor of medicine, and Zarour, along with colleagues at the National Institutes of Health, were launching a clinical trial that aimed to do that.

Mounting evidence in animal and human studies suggested links between the lineup of species in the brigade of bacteria that live in the gut—the “gut microbiome”—and responses to certain immunotherapies, in particular, therapies targeting the inhibitory immune checkpoint known as programmed death-1 (PD-1).

So Zarour, Davar and their colleagues set out to test whether modifying the microbiome could make immunotherapy work. Their study, supported by the National Cancer Institute and Merck, involved transferring fecal matter from patients whose melanoma responded to immunotherapy into patients like Reittinger, whose cancers had not.

Therapeutically transferring poop—a procedure called fecal microbial transplantation, or FMT—isn’t as outlandish as it may sound. Chinese practioners used this treatment more than 1,500 years ago. Infectious disease specialists have recognized FMT as the most effective treatment for severe diarrhea and colitis (an inflammation of the colon) caused by Clostridioides difficile. C. diff. colitis causes half a million infections in the United States each year, and in some older patients, it is a significant cause of death. FMT is widely used for the treatment of this colitis; although following reports of multiple cases of life-threatening infections, the U.S. Food and Drug Administration recently issued a caution regarding its use. Hence, in their trial, Davar and Zarour tested both donors and recipients extensively for potentially transmissible organisms.

Based on the promising data generated by Davar and Zarour, Reittinger’s physician, John Kirkwood, Distinguished Professor of Medicine at Pitt and coleader of the UPMC Melanoma Program, recommended that Reittinger enroll in the clinical trial. Reittinger says he didn’t need much convincing to sign on as the study’s first subject. It certainly sounded bizarre, he says, but Davar’s explanation of FMT—and the absence of other treatment alternatives—reassured him. “I told them, ‘OK, sounds cool—as long as you think it’s going to work,’” he recalls.

“Hey, I’m game for anything.”

He admits, however, that the reality of the situation was a bit jarring. A gastroenterologist at UPMC Shadyside Hospital performed the transfer using a colonoscope—a flexible tube inserted through the rectum. Reittinger was put under conscious sedation, but the drugs had minimal effects on him. And the room was full of clinicians observing the first-ever use of FMT to treat cancer in the United States.

“When I saw the big tube they were going to stick up my butt, and I had an audience of 20 people watching, I thought, ‘What the hell did I get myself into!?’” he recalls.

As the researchers reported in the journal Science in February, the study was a remarkable success. Six out of 15 participants for whom immunotherapy previously didn’t work benefited from it after receiving FMT. In three of those participants, the cancer went into remission, and in another three it stabilized and stopped growing. Reittinger was in the first group. He received his last immunotherapy treatment in June 2020, and though his cancer might not be completely gone—“there’s still what they call nonmeasurable nodules in my lungs,” he explains—now so small that they are undetectable by routine scans. “I can’t complain,” he says.

Davar was not surprised that the intervention worked, but he was amazed that FMT alone, with no other interventions, would be so effective. “We always believed the signal was there,” he  says. “But we did not think that a single FMT transfer would have produced such durable responses—especially given that we did not alter anything else.”

The trial provides intriguing data, says Davar, but it included few patients and the findings raise many questions. He and Zarour have already obtained funding to continue testing FMT in larger trials in patients with advanced melanoma and lung cancer. What’s still unknown, though, is how exactly the microbiome exerts its influence. Scientists know that the area surrounding the tumor— the “tumor microenvironment”—produces molecules that help cancer cells hide from the immune system.

But recent work shows that some factors may act more distantly: “And that may be how the gut microbiome comes into play here,” says Zarour. They suspect that certain key bacteria in the gut set up a signaling cascade that can dampen the ability of immunotherapy drugs like PD-1 inhibitors.

“When you don’t have these adverse bugs—or you get rid of these bugs—you remove the barrier that prevents PD-1 inhibitors from working,” says Davar. Through more studies in humans and animals, Davar and Zarour hope to further elucidate this mechanism in melanoma and other cancers and to pinpoint exactly which bacteria are beneficial so that more targeted forms of bacteria than FMT can be developed and tested in cancer patients.

Diagram of how gut bacteria changed post fecal matter transplants.

Microbial Moonshots

Timothy Hand on a magenta backgroundThe hints they have now, however, are the tip of the iceberg in a vast new field that scientists are just beginning to explore. Timothy Hand, assistant professor of pediatrics at Pitt, is taking a different approach to studying how the microbiome might affect the immune system’s response to cancer. He studies not the fecal microbiome but the microbes that live in the mucus lining the intestine. Because they rub up right against the lining, “those are the bacteria your immune system deals with directly and the ones that induce immune responses,” he says. They took the mucosal bacterium Helicobacter hepaticus and set out to see how its presence in the lining affects colorectal tumors that form there.

Why choose H. hepaticus? It causes inflammation in mice that are prone to inflammatory bowel disease, so Hand assumed the microbe would worsen colorectal tumors.

“It turns out we were 100% wrong about that,” he says.

Instead, tumors in those mice shrunk and the mice lived much longer. “It was like a protective therapy, caused by the transfer of just one bug.” In a paper under review, he and his colleagues report that the bacteria appear to be powering up helpful immune cells called T cells, which then promote the formation of cellular clusters called tertiary lymphoid structures, which, finally, in turn spur a strong anti-tumor immune response.

This mechanism might provide a fairly direct model for understanding the microbiome’s role in cancer, Hand says.

“You’re using a specific component of the microbiome to supercharge immunotherapy of the colon. And by identifying the bacteria that does this in humans, we could design a widely usable microbiome that helps antitumor immunotherapy and use it like a pill,” he says.

Tullia Bruno with a blue backgroundHe is collaborating with Tullia Bruno, assistant professor of immunology, to see how H. hepaticus correlates with colorectal cancer outcomes and with the formation of those lymphoid structures within tumors. These structures are similar to the normal lymphoid organs in your body, like tonsils and lymph nodes, where immune cells are educated, but in tumors they form slightly differently than normal. “These structures really do correlate with better prognosis and better response to immunotherapy,” Bruno says.

If their presence aligns with the bacterium, that might suggest that H. hepaticus can help people with colorectal cancer. “That would be the moonshot,” Hand says, adding that narrowing a particular clinical effect to distinct microbes and homing in on the mechanism would help anchor the field. The move from mouse to human isn’t straightforward, because the microbial species that inhabit the bodies of these two animals are different. But the work strongly hints that researchers may have to look beyond the fecal microbiome, even though it’s the easiest to sample. The mucosal microbiome offers a better bet for success, according to Hand, yet it’s much tougher to access because doing so requires a biopsy that’s generally taken during a colonoscopy.

Hand and Bruno aren’t entirely sure how the improvements that Davar and Zarour saw in their study relate to what they see. Perhaps there is enough H. hepaticus in the fecal microbiome to exert an effect, even at a distance from tumors; or perhaps something entirely different is going on. They hope that mouse studies, in which cancer progression and microbiome composition can be monitored over time, might reveal some clues. Reittinger has no doubt that scientists will eventually zero in on just how the microbiome plays a role.

“The world of cancer is changing,” he says. “From the time I initially started treatment five years ago to today, they aren’t even using the same drugs anymore.” He knows that people will benefit from that progress.

Diagaram from "Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients,” Diwakar Davar et. al. Science, 5 Feb 2021, Vol 371, Issue 6529, p. 595-602. Reprinted with permission from AAAS.