Experimental Fecal Transplant Saves Man with Terminal Cancer

In the spring of 2022, Tim Story’s doctor told him that he likely had just months to live.

Story, a high school football coach in Hattiesburg, Mississippi, had been diagnosed with Stage 3 small bowel cancer two years earlier, at the age of 49, after mysterious pains in his side turned out to be a tumor in his small intestine. Surgery and several grueling rounds of chemotherapy and immunotherapy had failed to stop the cancer, which had spread to other organs.

“I’m not a crying man, but my wife and I shed some tears on the couch that day,” said Story, now 53.

There was one final option, however: He could join an unusual clinical trial at MD Anderson Cancer Center in Houston that had just started recruiting patients. Highly experimental — and with no guarantee of success — the trial involved getting a so-called fecal transplant from a patient with advanced cancer who had been completely cured by immunotherapy. The idea was that the unique populations of gut bacteria found within the stool might help kick-start the immune system to better recognize and fight the cancer.

It came with its own risks, but Story agreed to enroll in the trial. “I knew I was kind of a guinea pig, but the only other option was staying at home, and I wasn’t going to make it,” he said.

Story didn’t know it at the time, but his participation in the trial would help advance a new frontier of cancer medicine: using the gut microbiome to unleash the full potency of the immune system.

The immune system and the microbiome

Early on in his treatment, Story was given an immunotherapy drug called a PD-1 inhibitor. Unlike other types of cancer treatments, immunotherapies harness the patient’s own immune system to fight the tumor.

PD-1 inhibitors have been shown to be particularly effective in patients with a type of tumor that has an unusually large number of DNA mutations compared with other tumors. Such tumors are classified as “microsatellite instability-high,” or MSI-H.

An estimated 20% of small bowel cancers and 20%-30% of endometrial cancers are MSI-H, as are some melanomas and ovarian cancers.

According to Dr. Tim Yeatman, associate director of translational research at Tampa General Hospital Cancer Institute in Florida, PD-1 inhibitors help unleash the immune system to spot these mutations and attack the tumor.

“They’re miraculous drugs,” Yeatman said. “They’ve been able to cure people with no chemotherapy, no radiotherapy or no surgery.”

In some cases, Yeatman said, patients experience improvements that are barely believable: people with mere months to live who are then cured of their disease. In medical parlance, this is referred to as a “complete response.”

Still, the drugs don’t always work. While clinical trials of PD-1 inhibitors in small bowel cancer have been limited, several studies have found that more than half of patients with advanced disease don’t respond to them, even if their tumors are MSI-H.

Story’s tumor was MSI-H, but when he was first given PD-1 inhibitors, the drugs made little noticeable difference.

So why do some patients react so well while others don’t? Oncologists have come to believe that the difference can be found in the complex synergy of the gut microbiome and the immune system.

That gut microbes and the immune system are interconnected is not a new idea: Research has suggested that certain gut microbes may be capable of activating cancer-fighting immune cells and stimulating other parts of the immune system to infiltrate tumors.

“We’ve seen in various studies that different microbial features seem to define treatment responders from nonresponders,” says Dr. Oriana Miltiadous, a pediatric oncologist and microbiome researcher at Memorial Sloan Kettering Cancer Center in New York City who was not involved with Story's clinical trial.

That raised the question: What if the unique mix of gut microbes from a patient who responded to the drugs could be replicated in a nonresponding patient? To transfer these bacteria, doctors take the stool from the patient with the complete response — known as a superdonor — and transplant it into the gut of the nonresponder. The procedure is known as a fecal transplant.

In a landmark trial published in 2021, oncologists at several cancer centers across the U.S. and in Israel gave fecal transplants to 10 patients with metastatic melanoma to try and improve their responses to PD-1 inhibitors. Three responded to the treatment, and one patient went on to be cancer-free.

The superdonor

It was Story’s good fortune, then, that Dr. Michael Overman, an oncologist at MD Anderson who focuses on pancreatic and intestinal tumors, had recently encountered a superdonor: an elderly woman, with metastatic colorectal cancer, who had been cured by PD-1 inhibitors.

“She had an amazing response,” Overman said. “Her tumors had been growing, and they suddenly shrank by 90%, to the extent where we could do surgery to get rid of the last little bit.”

The woman’s response inspired Overman to launch his own trial of 15 patients with MSI-H tumors, including Story, all of whom had various forms of metastatic cancer: colorectal, small bowel, brain, pancreatic and endometrial.

Over the course of a month, the 15 patients received repeated infusions of the superdonor’s stool into their bowels, with five of them getting additional oral doses, freeze-dried and put into capsules, for another six months. At the same time, Overman began to readminister the PD-1 inhibitors — a course of treatment that would continue for the next year — and waited to see what would happen.

It was around 18 months later, in the fall of 2023, that Story began to notice a tone of optimism in Overman’s voice. The fecal transplant, combined with PD-1 inhibitors, had triggered a remarkable shift in his body, and his tumors were starting to disappear. By the fall of 2024, he was declared cancer-free.

“By then, they were pretty definitive that the cancer had gone away,” Story said. “For me and my wife, it felt like winning the lottery, because before the trial we had no options left.”

Not all of the participants were as fortunate. Of the other 14, three had partial responses, with their cancer temporarily going into remission following the procedure — in two cases for more than a year.

Dr. Jonathan Jacobs, a gastroenterologist and microbiome researcher at the University of California, Los Angeles, described the overall results as remarkable, given that all of these patients had advanced cancer and mere months to live.

“These early reports of patients who were previously immunotherapy-resistant but experienced clinical response after receiving FMT [fecal transplants] and immunotherapy retreatment are very exciting,” said Jacobs, who wasn’t involved with the trial. “They demonstrate that gut microbiota is contributing to immunotherapy resistance in at least some patients, and provide hope that by changing the microbiome, some will respond.”

Scaling up

While fecal transplants represent a starting point, Overman is keen to transition toward a more nuanced approach to modifying the gut microbiome in cancer patients, noting the limitations of relying on superdonors.

“It’s a brute-force approach,” Overman said. “But you can’t scale it. This one patient can’t donate for the world. But the trial has shown how powerful the interplay is between the gut and the immune system. If we can figure that out and leverage it, we might be able to enhance the immune activity of cancer patients in general.”

To explore this, MD Anderson has partnered with Kanvas Biosciences, a biotechnology startup that developed a tool called HiPR-FISH that analyzes the relationships between gut microbes and immune response.

Using this technology to analyze the superdonor’s stool, Kanvas Biosciences was able to identify key microbial strains and put them into a pill that will be used in upcoming clinical trials at MD Anderson and other cancer centers across North America to see whether it can help prime the immune system to PD-1 inhibitors on a larger scale.

“We have essentially made a synthetic version of the superdonor stool and then optimized and immortalized it so that it can be reproduced and used in the treatment of cancer patients worldwide,” said Matthew Cheng, a trained medical microbiologist and the company’s co-founder.

Other oncologists are investigating their own ways to improve responses to cancer treatment through the gut microbiome.

At Memorial Sloan Kettering, Miltiadous has identified certain species of gut microbes that seem to be linked with better responses to cancer vaccines and could be potentially administered as part of a probiotic. After she has carried out initial experiments in mice, she is hoping to trial the combination of this probiotic and a cancer vaccine in children with neuroblastoma, a rare cancer that develops in nerve cells.

The results of the MD Anderson trial have prompted some researchers to wonder whether it will be possible to one day turn all immunotherapy nonresponders into responders, through a personalized medicine approach that delivers precisely the right microbes for a particular patient.

“It’s possible that even better outcomes could be obtained with a more precise understanding of the recipient’s microbiome, genetics, type of cancer, and antitumor immune responses, so select the optimal combinations,” Jacobs said.

For Story, the transformation in his fortunes has been dramatic.

“I’m a Christian, and I believe God got me through this for whatever reason because he’s got something else planned for me,” he said. “This past fall, I’ve been able to go back to work for the first time in four years. I’m back coaching football and teaching schools. It’s my passion. I’ve missed it so much because I had to retire. Now it feels like I’ve had a second chance at life.”