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.