Researchers at UPMC Hillman Cancer Centre, the University of Pittsburgh School of Medicine, the National Cancer Institute (NCI), Oregon State University and the National Institute of Allergy and Infectious Diseases, demonstrate that changing the gut microbiome can transform patients with advanced melanoma who never responded to immunotherapy – which has a failure rate of 40% for this type of cancer – into patients who do.
In this study, a team of researchers from UPMC Hillman 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 clinical and immunological outcomes. Collaborators at NCI 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 Dr Diwakar Davar, a medical oncologist and member of the Cancer Immunology and Immunotherapy Programme (CIIP) at UPMC Hillman and assistant professor of medicine at the University of Pittsburgh School of Medicine. “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 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.
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 stabilization 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 study co-senior author Dr Hassane Zarour, a cancer immunologist and co-leader of the CIIP at UPMC Hillman as well as a professor of medicine at Pitt. “So, any positive response should be attributable to the administration of faecal transplant.”
Analysis of samples taken from FMT recipients in this 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 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 that’s still several years away.
“Even if much work remains to be done, our study raises hope for microbiome-based therapies of cancers,” said Zarour, who holds the James W and Frances G McGlothlin chair in melanoma immunotherapy research at UPMC Hillman.
Funding for this study was provided by Merck and the National Cancer Institute (NCI).
Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients
Diwakar Davar, Hassane M Zarour, Amiran Dzutsev, John McCulloch, Richard Rodriguez, Jonathan Badger, Marie Vetizou, Alicia Cole, Miriam Fernandes, Stephanie Prescott, Rachel Costa, Ascharya Balaji and Giorgio Trinchieri, Joe-Marc Chauvin, Robert Morrison, Richelle Deblasio, Carmine Menna, Quanquan Ding, Ornella Pagliano, Bochra Zidi, Shuowen Zhang, Hong Wang, Scarlett Ernst, Amy Rose, Yana Najjar, John Kirkwood, Andrey Morgun, Ivan Vujkovic-Cvijin, Yasmine Belkaid, Amir Borhani, Marc Schwartz, Howard Dubner
Published in Science on 5 February 2021
Anti–programmed cell death protein 1 (PD-1) therapy provides long-term clinical benefits to patients with advanced melanoma. The composition of the gut microbiota correlates with anti–PD-1 efficacy in preclinical models and cancer patients. To investigate whether resistance to anti–PD-1 can be overcome by changing the gut microbiota, this clinical trial evaluated the safety and efficacy of responder-derived fecal microbiota transplantation (FMT) together with anti–PD-1 in patients with PD-1–refractory melanoma. This combination was well tolerated, provided clinical benefit in 6 of 15 patients, and induced rapid and durable microbiota perturbation. Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes. Collectively, our findings show that FMT and anti–PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti–PD-1 in a subset of PD-1 advanced melanoma.
University of Pittsburgh School of Medicine material
Science study (Restricted access)