Clinical studies are testing whether cancer immunotherapy drugs work better when patients receive a fecal transplant.
Jeff McIntosh/The Canadian Press/AP Photo
By Jocelyn Kaiser
ATLANTA—Oncologists deploy an array of strategies to stop cancer, from chemotherapy to radiation to drugs that boost the body’s immune defenses. Now, another potential therapy is being tested in clinical studies: fecal transplants. Early results from two groups described at the annual meeting of the American Association for Cancer Research (AACR) here this week suggest some patients who initially did not benefit from immunotherapy drugs saw their tumors stop growing or even shrink after receiving a stool sample from patients for whom the drugs worked. However, researchers caution, the results are preliminary.
During a fecal transplant, a stool sample from a healthy donor is moved into the gut of a sick person. The idea is that gut microbes from the healthy person will populate the sick person’s gut and improve their health. Fecal transplants are already an approved treatment for stubborn colon infections of the bacterium Clostridium difficile. But until now, fecal transplants haven’t been tested as part of cancer therapy.
Although the two studies have so far followed only a handful of patients for a few months, researchers say their initial results are exciting. “This is the first clinical evidence that you may have an impact on antitumor immunity and potentially even responses,” says melanoma researcher Jennifer Wargo of MD Anderson Cancer Center in Houston, Texas, who is leading a similar clinical trial just getting underway.
The research involves drugs that block PD-1, a protein on the surface of immune cells known as T cells. The protein shuts off these immune soldiers’ ability to fight pathogens and other foreign invaders, and tumors can stimulate PD-1 to shield themselves. PD-1 blockers have put some patients’ cancer into remission for years, but most cancers don’t respond.
In the past few years, researchers have reported a tentative connection between response levels and the bacteria, viruses, and other microbes in our gut collectively known as the microbiome. The gut microbiomes differ between patients for whom PD-1 blockers work and those for whom they don’t. What’s more, patients who take antibiotics (which temporarily wipe out gut microbiota) prior to or soon after receiving PD-1 blockers tend to see less success. Experiments in tumor-bearing mice have also shown the drugs worked better after the rodents got a fecal transplant from human patients whose tumors shrank after they received the drugs.
That inspired an Israeli team to test the idea in people. The group, led by Gal Markel at Sheba Medical Center in Ramat Gan, Israel, collected stool samples from two patients with metastatic melanoma, or skin cancer that had spread, whose tumors vanished after they got the PD-1 drugs. The team then transferred their feces via colonoscopy to three patients with the same kind of cancer whose tumors seemed impervious to PD-1 drugs. The team also gave the recipients oral pills containing the donors’ dried stool.
The gut microbiomes of all three patients changed to more closely match the genetic makeup of the stool donors’ gut microbiomes, clinician and graduate student Erez Baruch reported at the AACR meeting. And in two recipients, the donated microbes appeared to boost their cancers’ responses to PD-1 drugs. One patient’s tumors got smaller, though new ones did appear 2 months after the transplant. Another patient’s tumors eventually shrank, and the man is still doing well after 7 months. Examining biopsies of gut and tumor tissue, the researchers found that posttransplant, the patients’ guts had more of a type of immune cell that senses invaders and activates the immune system; these cells had also infiltrated their tumors along with T cells, indicating that their previously “cold” tumors had become “hot,” or visible to the immune system.
Another team is also seeing hints of success, collaborator Giorgio Trinchieri of the National Cancer Institute in Bethesda, Maryland, reported at the meeting. In that trial, which gave three participants donor stool via colonoscopy and then PD-1 drugs, one patient who started treatment 10 months ago has seen their tumors shrink. Another patient’s tumors neither shrank nor grew after 3 months of treatment.
“The data is similar [in the two studies], which suggests there is a signal,” says oncologist Diwakar Davar of the University of Pittsburgh in Pennsylvania, who is running the trial with lead investigator Hassane Zarour. “The approach is promising, but we need more clinical and mechanistic data before we can claim it’s working.” Davar says it’s possible the patients’ tumors would have eventually responded to the drugs without the fecal transplant, although that has rarely been reported to happen when treatment doesn’t work early on.
One unresolved question is exactly which microbes help ramp up the desired immune activity. In previously published studies, patients in four cities whose tumors responded to the drugs, for example, had widely varying gut microbiomes, possibly because of differences in diet and climate, Trinchieri notes. And Wargo’s team member Christine Spencer of the Parker Institute for Cancer Immunotherapy in San Francisco, California, reported in a poster here that, surprisingly, patients who take probiotics—pills that supposedly contain beneficial gut bacteria—do worse on PD-1 drugs than those who don’t. The bottom line: Researchers still have a lot to learn.
Source: Science Mag