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Researchers at UPMC Hillman Cancer Center and the National Cancer Institute (NCI) show that changing the gut microbiome can turn patients with advanced melanoma who have never responded to immunotherapy – with a 40% failure rate for this type of cancer – into patients who do this.

The results of this Phase II clinical trial demonstrating the principle were published online in Science today. In this study, a team of UPMC Hillman 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 followed the clinical and immunological results . NCI staff analyzed microbiome samples from these patients to understand why FMT appears to enhance their response to immunotherapy.

“FMT is just a means to an end,” said the study co-lead author, Diwakar Davar, MD, a medical oncologist and a member of the Cancer Immunology and Immunotherapy Program (CIIP) at UPMC Hillman and assistant professor of medicine at the University of Pittsburgh Medical Faculty. “We know that the composition of the gut microbiome – gut bacteria – can alter the likelihood of responding to immunotherapy. But what are ‘good’ bacteria? An individual’s microbiome contains about 100 trillion gut bacteria and 200 times more bacterial genes than all of their cells together. “

Fecal transplantation provides a way to capture a multitude of candidate microbes and test trillions at a time to see if the “good” bacteria on board could sensitize more people to PD-1 inhibitors. This study is among the first to test this idea in humans.

Davar and colleagues collected stool samples from patients who responded extremely well to anti-PD-1 immunotherapy and tested them for infectious pathogens before giving the samples by colonoscopy to advanced melanoma patients who had never responded to immunotherapy before. The patients then received the anti-PD-1 drug pembrolizumab. And it worked.

A fecal transplant alters the gut microbiome and turns non-responders to cancer immunotherapy into responders. Image credit: UPMC

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

“The likelihood that the patients treated in this study will respond spontaneously to a second administration of anti-PD-1 immunotherapy is very small,” said co-senior author of the study, Hassane Zarour, MD, a cancer immunologist and co -Head of CIIP at UPMC Hillman and Professor of Medicine at Pitt. “Therefore, any positive reaction should be due to the administration of a fecal transplant.”

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

Davar and Zarour hope to do a larger study in melanoma patients to evaluate whether FMT can be effective in treating other cancers. Ultimately, their goal is to replace FMT with pills that contain a cocktail of the most beneficial microbes to promote immunotherapy – but that’s still a few years away.

“While there is still much work to be done, our study raises hope for microbial-based cancer therapies,” said Zarour, who holds the Chair in Melanoma Immunotherapy Research of James W. and Frances G. McGlothlin at UPMC Hillman.

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More information:
Science (2021). DOI: 10.1126 / science.abf3363 Provided by the University of Pittsburgh

Quote: A fecal transplant transforms cancer immunotherapy non-responders into responders (2021, February 4), which will be released on February 4, 2021 from responders.html were retrieved

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