@article{c2f4ee85d5a344498b32d0a1918280c9,
title = "Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients",
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.",
author = "Diwakar Davar and Dzutsev, {Amiran K.} and McCulloch, {John A.} and Rodrigues, {Richard R.} and Chauvin, {Joe Marc} and Morrison, {Robert M.} and Deblasio, {Richelle N.} and Carmine Menna and Quanquan Ding and Ornella Pagliano and Bochra Zidi and Shuowen Zhang and Badger, {Jonathan H.} and Marie Vetizou and Cole, {Alicia M.} and Fernandes, {Miriam R.} and Stephanie Prescott and Costa, {Raquel G.F.} and Balaji, {Ascharya K.} and Andrey Morgun and Ivan Vujkovic-Cvijin and Hong Wang and Borhani, {Amir A.} and Schwartz, {Marc B.} and Dubner, {Howard M.} and Ernst, {Scarlett J.} and Amy Rose and Najjar, {Yana G.} and Yasmine Belkaid and Kirkwood, {John M.} and Giorgio Trinchieri and Zarour, {Hassane M.}",
note = "Funding Information: The clinical trial (NCT03341143) was supported by a research contract from Merck MSD to D.D. D.D. is supported by the Melanoma Breakthrough Foundation Breakthrough Consortium. H.M.Z. is supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) (award numbers R01 CA228181 and R01 CA222203) and the James W. and Frances G. McGlothlin Chair in Melanoma Immunotherapy Research. Work of the UPMC Hillman Cancer Center Microbiome Shared Facility and Cytometry Facility is supported by the NIH NCI Comprehensive Cancer Center Support CORE grant (P30 CA047904). This research was supported in part by the University of Pittsburgh Center for Research Computing and Unified Flow Cytometry Core of the University of Pittsburgh's Department of Immunology through the resources provided. This work was supported in part by the Intramural Research Program of the NIH, NIAID, and NCI Center for Cancer Research. Publisher Copyright: {\textcopyright} 2021 American Association for the Advancement of Science. All rights reserved.",
year = "2021",
month = feb,
day = "5",
doi = "10.1126/science.abf3363",
language = "English (US)",
volume = "371",
pages = "595--602",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6529",
}
