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PITTSBURGH, February 4, 2021 – Researchers at UPMC Hillman Cancer Center and the National Cancer Institute (NCI) show that changing the gut microbiome can transform patients with advanced melanoma who have never responded to immunotherapy – which has a 40% failure rate for this type of cancer – in patients who do.
The results of this proof-of-principle phase II clinical trial were published online today in Science. In this study, a team of researchers from UPMC Hillman administered fecal microbiota (FMT) transplants and anti-PD-1 immunotherapy to melanoma patients who had failed all available therapies, including anti-PD-1, then followed the clinical and immunological results. NCI collaborators analyzed microbiome samples from these patients to understand why FMT appears to stimulate their response to immunotherapy.
“FMT is just a means to an end,” said Diwakar Davar, MD, study co-lead author, medical oncologist and member of the Cancer Immunology and Immunotherapy (CIIP) Program. at UPMC Hillman and Assistant Professor of Medicine at the University of Pittsburgh. Medicine School. “We know that the makeup of the gut microbiome – the gut bacteria – can affect the likelihood of responding to immunotherapy. But what are “good” bacteria? There are approximately 100 trillion gut bacteria and 200 times more bacterial genes in an individual’s microbiome than in all of their cells combined. ”
Fecal transplantation offers a way to capture a wide range of candidate microbes, testing billions of billions at a time, to see if having the “good” bacteria on board could make more people susceptible to PD inhibitors. -1. This study is among the first to test this idea in humans.
Davar and his colleagues collected fecal samples from patients who responded extraordinarily well to anti-PD-1 immunotherapy and tested for infectious pathogens before giving the samples, by colonoscopy, to patients with advanced melanoma who n ‘had never responded to immunotherapy before. The patients then received the anti-PD-1 drug pembrolizumab. And it worked.
Of 15 patients with advanced melanoma who received combined FMT and anti-PD-1 therapy, six experienced tumor shrinkage or disease stabilization for more than a year.
“The likelihood that patients treated in this trial will respond spontaneously to a second administration of anti-PD-1 immunotherapy is very low,” said study co-author Hassane Zarour, MD, cancer immunologist and CIIP co-leader at UPMC Hillman as well as professor of medicine at Pitt. “So any positive response should be attributable to the administration of a fecal transplant.”
Analysis of samples taken from FMT recipients in this study revealed immunologic changes in blood and at tumor sites suggesting increased activation of immune cells in responders as well as increased immunosuppression in non-responders. . Artificial intelligence has linked these changes to the gut microbiome, likely caused by FMT.
Davar and Zarour hope to conduct a larger trial with melanoma patients, as well as to assess 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 to boost immunotherapy – but that’s still several years away.
“While a lot of work remains to be done, our study holds promise for microbiome-based cancer therapies,” said Zarour, James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research. ‘UPMC Hillman.
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Other authors of the study include Amiran Dzutsev, MD, John McCulloch, Ph.D., Richard Rodriguez, MBA, Jonathan Badger, Ph.D., Marie Vetizou, Ph.D., Alicia Cole, Miriam Fernandes, Ph.D., Stephanie Prescott, MSN, CRNP, Rachel Costa, MS, Ascharya Balaji and Giorgio Trinchieri, MD, of the National Cancer Institute; Joe-Marc Chauvin, Ph.D., Robert Morrison, MD, Richelle Deblasio, Carmine Menna, Quanquan Ding, Ph.D., Ornella Pagliano, Bochra Zidi, Ph.D., Shuowen Zhang, Hong Wang, Ph.D. , Scarlett Ernst, Amy Rose, Yana Najjar, MD, and John Kirkwood, MD, of UPMC Hillman Cancer Center; Andrey Morgun, MD, Ph.D., Oregon State University; Ivan Vujkovic-Cvijin, Ph.D., and Yasmine Belkaid, Ph.D., from the National Institute of Allergies and Infectious Diseases; and Amir Borhani, MD, Marc Schwartz, MD, and Howard Dubner, MD, of Pitt.
Funding for this study was provided by Merck and the NCI (R01 CA222203 and P30 CA047904).
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About the UPMC Hillman Cancer Center
UPMC Hillman Cancer Center is the only National Cancer Institute designated Comprehensive Cancer Center in the region and one of the largest integrated community cancer networks in the United States. Supported by the collective strength of UPMC – which is ranked # 15 in cancer care nationwide by US News & World Report – and the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center has nearly 80 sites across Pennsylvania, Ohio, New York and Maryland, with cancer centers and international partnerships. The more than 2,000 physicians, researchers and staff are leaders in the fields of molecular and cellular cancer biology, cancer immunology, cancer virology, biological cancer control and the epidemiology, prevention and therapy of cancer. The UPMC Hillman Cancer Center is transforming cancer research, care and prevention – one patient at a time.
About the University of Pittsburgh School of Medicine
As one of the nation’s leading academic biomedical research centers, the University of Pittsburgh School of Medicine integrates cutting-edge technology with basic science across a wide range of disciplines in an ongoing quest to harness the power new knowledge and improve the human condition. Driven primarily by the School of Medicine and its affiliates, Pitt has been ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt placed fifth among all universities. US federal total. support for research and development in science and engineering.
Likewise, the School of Medicine is also committed to advancing the quality and strength of its medical and academic education programs, for which it is recognized as an innovative leader, and to training highly skilled and compassionate clinicians and creative scientists well equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position healthcare as an engine of the region’s economy. For more information on the School of Medicine, see http: // www.
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