Changing gut microbiome via fecal transplant shifts immunotherapy response

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A new study demonstrates that changing the gut microbiome can transform patients with advanced melanoma who never responded to immunotherapy into patients who do, according to research by the University of Pittsburgh Hillman Cancer Center and the National Cancer Institute published in the journal Science.

For the study, a proof-of-principle phase II clinical trial, researchers administered fecal microbiota transplants (FMT) and anti-PD-1 immunotherapy to melanoma patients who had failed all available therapies, including anti-PD-1, and then tracked clinical and immunological outcomes. Researchers analyzed microbiome samples from these patients to understand why FMT seems to boost their response to immunotherapy.

Fecal transplant offers a way to capture a wide array of candidate microbes, testing trillions at once, to see whether having the "good" bacteria on board could make more people sensitive to PD-1 inhibitors. This study is among the first to test that idea in humans, the authors said.

The researchers collected fecal samples from patients who responded extraordinarily well to anti-PD-1 immunotherapy and tested for infectious pathogens before giving the samples, through colonoscopy, to advanced melanoma patients who had never previously responded to immunotherapy. The patients were then given the anti-PD-1 drug pembrolizumab, which then worked.

Out of 15 advanced melanoma patients who received the combined FMT and anti-PD-1 treatment, six showed either tumor reduction or disease stabilization lasting more than a year, according to the study.

Analysis of samples taken from FMT recipients in this study revealed immunologic changes in the blood and at tumor sites suggesting increased immune cell activation in responders as well as increased immunosuppression in non-responders. Artificial intelligence linked these changes to the gut microbiome, likely caused by FMT.

The researchers said they hope to run a larger trial with melanoma patients, as well as evaluating whether FMT may be effective in treating other cancers. Ultimately, their goal is to replace FMT with pills containing a cocktail of the most beneficial microbes for boosting immunotherapy, but they said that's still several years away.

“FMT is just a means to an end,” said Diwakar Davar, MD, study co-lead author, a medical oncologist at the Cancer Immunology and Immunotherapy Program, and assistant professor of medicine at the University of Pittsburgh School of Medicine, in a statement. “We know the composition of the intestinal microbiome, gut bacteria, can change the likelihood of responding to immunotherapy. Even if much work remains to be done, our study raises hope for microbiome-based therapies of cancers.”