Journal
SCIENCE
Volume 371, Issue 6529, Pages 595-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abf3363
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Funding
- Merck MSD
- Melanoma Breakthrough Foundation Breakthrough Consortium
- National Cancer Institute (NCI) of the National Institutes of Health (NIH) [R01 CA228181, R01 CA222203]
- James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research
- UPMC Hillman Cancer Center Microbiome Shared Facility
- NIH NCI Comprehensive Cancer Center Support CORE grant [P30 CA047904]
- University of Pittsburgh Center for Research Computing and Unified Flow Cytometry Core of the University of Pittsburgh's Department of Immunology
- Intramural Research Program of the NIH, NIAID, and NCI Center for Cancer Research
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The study demonstrated that fecal microbiota transplantation combined with anti-PD-1 therapy can overcome resistance to anti-PD-1 in a subset of PD-1 refractory melanoma patients, leading to clinical benefits. This approach induced changes in the gut microbiome and reprogrammed the tumor microenvironment, ultimately enhancing the efficacy of anti-PD-1 treatment.
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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