Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity.

Autor:	Glitza IC; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Seo YD; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Spencer CN; Parker Institute for Cancer Immunotherapy, San Francisco, California., Wortman JR; Seres Therapeutics, Cambridge, Massachusetts., Burton EM; Strategic Translational Research Initiative Development, The University of Texas MD Anderson Cancer Center, Houston, Texas., Alayli FA; Parker Institute for Cancer Immunotherapy, San Francisco, California., Loo CP; Parker Institute for Cancer Immunotherapy, San Francisco, California., Gautam S; Parker Institute for Cancer Immunotherapy, San Francisco, California., Damania A; Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas., Densmore J; Parker Institute for Cancer Immunotherapy, San Francisco, California., Fairchild J; Parker Institute for Cancer Immunotherapy, San Francisco, California.; Portage Biotech, Westport, Connecticut., Cabanski CR; Parker Institute for Cancer Immunotherapy, San Francisco, California., Wong MC; Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas., Peterson CB; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Weiner B; Seres Therapeutics, Cambridge, Massachusetts., Hicks N; Seres Therapeutics, Cambridge, Massachusetts., Aunins J; Seres Therapeutics, Cambridge, Massachusetts., McChalicher C; Seres Therapeutics, Cambridge, Massachusetts., Walsh E; Seres Therapeutics, Cambridge, Massachusetts., Tetzlaff MT; Department of Pathology, University of California San Francisco, San Francisco, California., Hamid O; Cutaneous Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California., Ott PA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Boland GM; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Sullivan RJ; Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts., Grossmann KF; Providence Cancer Institute Franz Clinic, Portland, Oregon., Ajami NJ; Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas., LaVallee T; Parker Institute for Cancer Immunotherapy, San Francisco, California.; Coherus BioSciences, Redwood City, California., Henn MR; Seres Therapeutics, Cambridge, Massachusetts., Tawbi HA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Wargo JA; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2024 Jul 01; Vol. 14 (7), pp. 1161-1175.
DOI:	10.1158/2159-8290.CD-24-0066
Abstrakt:	Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials. Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti-PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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