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Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity
Open accessPublished version of a preprint
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 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.
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FMT from ICI responders has demonstrated the ability to restore microbial diversity and re-establish antitumor activity.
“However, FMT from ICI responders has demonstrated the ability to restore microbial diversity and re-establish antitumor activity139,141,142.”
From Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors (2025) · cites this paper as [142]
The Introduction (page unavailable) reports that FMT from immunotherapy responders promoted response and overcame preexisting ICB resistance in melanoma, supporting the antitumor-response portion of the claim. Our copy does not say that responder FMT restored microbial diversity; the diversity results concern vancomycin preconditioning and SER-401, and the planned FMT arm never enrolled patients. (LLM, conf=0.88)
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Microbiome meets immunotherapy: unlocking the hidden predictors of immune checkpoint inhibitors
Huang, L., Li, Y., Zhang, C., Jiang, A., Zhu, L., Mou, W., Li, K., Zhang, J., Cui, C., Cui, X., et al. (2025) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00819-2 · Cited by 28
“However,FMTfromICIrespondershasdemonstratedthe ability to restore microbial diversity and re-establish antitumor activity 139,141,142 .”
Metadata
- Authors
- Glitza, I. C., Seo, Y. D., Spencer, C. N., Wortman, J. R., Burton, E. M., Alayli, F. A., Loo, C. P., Gautam, S., Damania, A., Densmore, J., Fairchild, J., Cabanski, C. R., Wong, M. C., Peterson, C. B., Weiner, B., Hicks, N., Aunins, J., McChalicher, C., Walsh, E., Tetzlaff, M. T., Hamid, O., Ott, P. A., Boland, G. M., Sullivan, R. J., Grossmann, K. F., Ajami, N. J., LaVallee, T., Henn, M. R., Tawbi, H. A., & Wargo, J. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Seres Therapeutics (United States) (US)
- University of California, San Francisco (US)
- Angeles Clinic and Research Institute (US)
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Harvard University (US)
- Providence Portland Medical Center (US)
- Coherus BioSciences (United States) (US)
- Corresponding author
- Wargo, Jennifer A.
- ORCID
- Glitza, Isabella C.
- Seo, Yongwoo David
- Spencer, Christine N.
- Wortman, Jennifer R.
- Burton, Elizabeth M.
- Alayli, Farah A.
- Loo, Christopher P.
- Gautam, Shikha
- Damania, Ashish
- Densmore, Julie
- Fairchild, Justin
- Cabanski, Christopher R.
- Wong, Matthew C.
- Peterson, Christine B.
- Weiner, Brian
- Hicks, Nathan
- Aunins, John
- McChalicher, Christopher
- Walsh, Emily
- Tetzlaff, Michael T.
- Hamid, Omid
- Ott, Patrick A.
- Boland, Genevieve M.
- Sullivan, Ryan J.
- Grossmann, Kenneth F.
- Ajami, Nadim J.
- LaVallee, Theresa
- Henn, Matthew R.
- Tawbi, Hussein A.
- Wargo, Jennifer A.
- Venue
- Cancer Discovery
- Published
- 2024-04-03
- Volume
- 14
- Issue
- 7
- Pages
- 1161-1175
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC11215408
- OpenAlex
- W4394581911
- Cited by
- 87
- References
- 17
- Citations by year
- 2026: 37 · 2025: 43 · 2024: 7
- FWCI
- 14.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Discovery (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Parker Institute for Cancer Immunotherapy
- University of Texas MD Anderson Cancer Center
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- gut microbiota modulation, metastatic melanoma, immune checkpoint blockade, nivolumab, antibiotic preconditioning, Ruminococcaceae, anti-PD-1 therapy, biomarker-stratified trial, microbiota-immune interactions, trial accrual
- MeSH terms
- Gastrointestinal Microbiome, Nivolumab, Immune Checkpoint Inhibitors, COVID-19, Adult, Aged, Anti-Bacterial Agents, Female, Humans, Male, Melanoma, Middle Aged, Skin Neoplasms, Biomarkers, Tumor, Vancomycin
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