Faecal transplant benefits cancer immunotherapy non-responders
Researchers at the University of Pittsburgh, the UPMC Hillman Cancer Center and the US National Cancer Institute (NCI) have demonstrated that changing the gut microbiome can transform patients with advanced melanoma who never respond to immunotherapy — which has a failure rate of 40% for this type of cancer — into patients who do. The results of the team’s proof-of-principle Phase 2 clinical trial were published in the journal Science.
In the study, researchers administered faecal microbiota transplants (FMT) and anti-PD-1 immunotherapy to melanoma patients who had failed all available therapies, including anti-PD-1, and then tracked outcomes. Collaborators at NCI then analysed microbiome samples from these patients to understand why FMT seems to boost their response to immunotherapy.
“FMT is just a means to an end,” said study co-lead author Diwakar Davar, Assistant Professor of Medicine at Pitt and member of the Cancer Immunology and Immunotherapy Program (CIIP) at UPMC Hillman. “We know the composition of the intestinal microbiome — gut bacteria — can change the likelihood of responding to immunotherapy. But what are ‘good’ bacteria? There are about 100 trillion gut bacteria and 200 times more bacterial genes in an individual’s microbiome than in all of their cells put together.”
Faecal transplants offer 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.
Davar and colleagues collected faecal 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, and it worked — out of 15 advanced melanoma patients who received the combined FMT and anti-PD-1 treatment, six showed either tumour reduction or disease stabilisation lasting more than a year.
“The likelihood that the patients treated in this trial would spontaneously respond to a second administration of anti-PD-1 immunotherapy is very low,” said co-senior author Hassane Zarour, a Professor of Medicine at Pitt and co-leader of CIIP. “So any positive response should be attributable to the administration of faecal transplant.”
Analysis of samples taken from FMT recipients in the study revealed immunologic changes in the blood and at tumour 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.
Davar and Zarour next hope to run a larger trial with melanoma patients and also evaluate whether FMT could 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 that’s still several years away.
“Even if much work remains to be done, our study raises hope for microbiome-based therapies of cancers,” Zarour said.
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