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      Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

      , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
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      American Association for the Advancement of Science (AAAS)

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          Abstract

          Pre-clinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR). Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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          Most cited references13

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          A mathematical theory of communication

          C. Shannon (2001)
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            Estimating and comparing time-dependent areas under receiver operating characteristic curves for censored event times with competing risks.

            The area under the time-dependent ROC curve (AUC) may be used to quantify the ability of a marker to predict the onset of a clinical outcome in the future. For survival analysis with competing risks, two alternative definitions of the specificity may be proposed depending of the way to deal with subjects who undergo the competing events. In this work, we propose nonparametric inverse probability of censoring weighting estimators of the AUC corresponding to these two definitions, and we study their asymptotic properties. We derive confidence intervals and test statistics for the equality of the AUCs obtained with two markers measured on the same subjects. A simulation study is performed to investigate the finite sample behaviour of the test and the confidence intervals. The method is applied to the French cohort PAQUID to compare the abilities of two psychometric tests to predict dementia onset in the elderly accounting for death without dementia competing risk. The 'timeROC' R package is provided to make the methodology easily usable. Copyright © 2013 John Wiley & Sons, Ltd.
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              Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

              Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity.
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                Author and article information

                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                January 04 2018
                January 05 2018
                January 05 2018
                November 02 2017
                : 359
                : 6371
                : 97-103
                Article
                10.1126/science.aan4236
                5827966
                29097493
                5c5e713c-a933-4afb-88d9-ced34fb10989
                © 2017

                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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