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. 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.

中文翻译：

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黑色素瘤中随机安慰剂对照、生物标志物分层 Ib 期微生物组调节：抗生素预处理对微生物组和免疫的影响

肠道微生物群调节有望改善免疫检查点封锁（ICB）反应；然而，缺乏精确的生物标志物驱动、安慰剂对照试验。我们使用 SER-401（一种口服富含厚壁菌门的孢子制剂）对未接受过 ICB 的转移性黑色素瘤患者进行了一项多中心、随机安慰剂对照、生物标志物分层 I 期试验。粪便微生物群特征在基线时进行了表征；在随机分配至 SER-401 组（口服万古霉素预处理/单独 SER-401/纳武单抗 + SER-401）与安慰剂组（安慰剂抗生素/安慰剂微生物组调节 (PMM)）之前，根据高瘤胃球菌科丰度与低瘤胃球菌丰度对患者进行分层/纳武单抗 + PMM (NCT03817125)]。对 14 名患者的分析表明，SER-401 + 纳武单抗治疗是安全的，SER-401 组的客观缓解率为 25%，安慰剂组为 67%（尽管该研究因应计效果不佳而缺乏说服力）在 COVID-19 大流行期间）。转化分析表明，万古霉素预处理与肠道微生物群破坏和免疫力受损有关，ICB 给药后恢复不完全（特别是在高基线瘤胃球菌科患者中）。这些结果对未来的微生物组调节试验具有重要意义。意义：这项首创、安慰剂对照、随机生物标志物驱动的微生物组调节试验表明，万古霉素 + SER-401 和抗 PD-1 对于黑色素瘤患者是安全的。尽管受到大流行期间应计效果不佳的限制，但通过转化分析获得了重要的见解，这表明在设计此类试验时应仔细考虑抗生素预处理和介入药物剂量方案。