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The University of Texas MD Anderson Cancer Center

Cancer Discov., Apr 04 2024, | https://doi.org/10.1158/2159-8290.CD-24-0066 Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity

Isabella C Glitza ^#,1, Yongwoo David Seo^#,2, Christine N Spencer ^#,3, Jennifer R Wortman ^#,4, Elizabeth M Burton ⁵, Farah A Alayli ³, Christopher P Loo ³, Shikha Gautam ³, Ashish Damania ⁶, Julie Densmore ³, Justin Fairchild ^3,7, Christopher R Cabanski ³, Matthew C Wong⁶, Christine B Peterson ⁸, Brian Weiner⁴, Nathan Hicks ⁴, John G Auniņš ⁴, Christopher McChalicher ⁴, Emily Walsh ⁴, Michael T Tetzlaff⁹, Omid Hamid ¹⁰, Patrick A Ott ^11,12, Genevieve M Boland ^13,14, Ryan J Sullivan ¹⁵, Kenneth F Grossmann¹⁶, Nadim J Ajami ⁶, Theresa LaVallee ^##,3,17, Matthew R Henn ^##,4, Hussein A Tawbi ^##,1, Jennifer A Wargo ^##,2,18

¹Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

²Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

³Parker Institute for Cancer Immunotherapy, San Francisco, California.

⁴Seres Therapeutics, Cambridge, Massachusetts.

⁵Strategic Translational Research Initiative Development, The University of Texas MD Anderson Cancer Center, Houston, Texas.

⁶Platform for Innovative Microbiome and Translational Research, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.

⁷Portage Biotech, Westport, Connecticut.

⁸Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

⁹Department of Pathology, University of California San Francisco, San Francisco, California.

¹⁰Cutaneous Oncology, The Angeles Clinic and Research Institute, A Cedars-Sinai Affiliate, Los Angeles, California.

¹¹Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

¹²Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

¹³Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.

¹⁴Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

¹⁵Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.

¹⁶Providence Cancer Institute Franz Clinic, Portland, Oregon.

¹⁷Coherus BioSciences, Redwood City, California.

¹⁸Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

^#I.C. Glitza, Y.D. Seo, C.N. Spencer, and J.R. Wortman contributed equally to this article.

^##T. LaVallee, M.R. Henn, H.A. Tawbi, and J.A. Wargo are the co-senior authors of this article.

^*Corresponding Author: Jennifer A. Wargo

Abstract

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 Firmicutes-enriched 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 objective response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was under-powered 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. 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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-18)
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