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Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients.

Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Genetics and Microbiome Core, Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA. Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD 20892, USA. Biostatistics Facility, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA. Division of Abdominal Imaging, Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15213, USA. Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. zarourhm@upmc.edu trinchig@mail.nih.gov. Department of Medicine and UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA. zarourhm@upmc.edu trinchig@mail.nih.gov. Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Science (New York, N.Y.). 2021;(6529):595-602
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Abstract

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.

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Publication Type : Clinical Trial

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