Fecal transplant changes the gut microbiome, turning cancer immunotherapy non-responders into responders.
Video Credits: UNIVERSITY OF PITTSBURGH
Researchers at UPMC Hillman Cancer Center and the National Cancer Institute (NCI) 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.
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 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 analyzed 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, M.D., a medical oncologist and member of the Cancer Immunology and Immunotherapy Program (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."
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.
Davar and colleagues 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. And it 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.
"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 Hassane Zarour, M.D., 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 fecal transplant."
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.
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.
Additional authors on the study include Amiran Dzutsev, M.D., John McCulloch, Ph.D., Richard Rodriguez, M.B.A., Jonathan Badger, Ph.D., Marie Vetizou, Ph.D., Alicia Cole, Miriam Fernandes, Ph.D., Stephanie Prescott, M.S.N., C.R.N.P., Rachel Costa, M.S., Ascharya Balaji and Giorgio Trinchieri, M.D., of the National Cancer Institute; Joe-Marc Chauvin, Ph.D., Robert Morrison, M.D., 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, M.D., and John Kirkwood, M.D., of UPMC Hillman Cancer Center; Andrey Morgun, M.D., Ph.D., of Oregon State University; Ivan Vujkovic-Cvijin, Ph.D., and Yasmine Belkaid, Ph.D., of the National Institute of Allergy and Infectious Diseases; and Amir Borhani, M.D., Marc Schwartz, M.D., and Howard Dubner, M.D., of Pitt.
Funding for this study was provided by Merck and the NCI (R01 CA222203 and P30 CA047904).
About UPMC Hillman Cancer Center
UPMC Hillman Cancer Center is the region's only National Cancer Institute-designated Comprehensive Cancer Center and is one of the largest integrated community cancer networks in the United States. Backed by the collective strength of UPMC--which is ranked No. 15 for cancer care nationally by U.S. News & World Report - and the University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center has nearly 80 locations throughout Pennsylvania, Ohio, New York, and Maryland, with cancer centers and partnerships internationally. The more than 2,000 physicians, researchers, and staff are leaders in molecular and cellular cancer biology, cancer immunology, cancer virology, biobehavioral cancer control, and cancer epidemiology, prevention, and therapeutics. 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 centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has 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 ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, 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 health care as a driving force behind the region's economy. For more information about the School of Medicine, see http://www.