Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto; Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network, Toronto.
Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
Ann Oncol. 2023 Jun;34(6):520-530. doi: 10.1016/j.annonc.2023.02.011. Epub 2023 Mar 1.
The intestinal microbiome has been associated with response to immune checkpoint inhibitors (ICIs) in humans and causally implicated in ICI responsiveness in animal models. Two recent human trials demonstrated that fecal microbiota transplant (FMT) from ICI responders can rescue ICI responses in refractory melanoma, but FMT has specific limitations to scaled use.
We conducted an early-phase clinical trial of a cultivated, orally delivered 30-species microbial consortium (Microbial Ecosystem Therapeutic 4, MET4) designed for co-administration with ICIs as an alternative to FMT and assessed safety, tolerability and ecological responses in patients with advanced solid tumors.
The trial achieved its primary safety and tolerability outcomes. There were no statistically significant differences in the primary ecological outcomes; however, differences in MET4 species relative abundance were evident after randomization that varied by patient and species. Increases in the relative abundance of several MET4 taxa, including Enterococcus and Bifidobacterium, taxa previously associated with ICI responsiveness, were observed and MET4 engraftment was associated with decreases in plasma and stool primary bile acids.
This trial is the first report of the use of a microbial consortium as an alternative to FMT in advanced cancer patients receiving ICI and the results justify the further development of microbial consortia as a therapeutic co-intervention for ICI treatment in cancer.
肠道微生物群与人类对免疫检查点抑制剂（ICIs）的反应有关，并在动物模型中被认为与 ICI 的反应性有关。最近的两项人类试验表明，来自 ICI 应答者的粪便微生物群移植（FMT）可以挽救难治性黑色素瘤对 ICI 的反应，但 FMT 在规模化应用方面具有特定的局限性。
我们开展了一项早期临床试验，评估了一种经培养的、口服给药的 30 种微生物联合体（微生物生态治疗 4，MET4），该联合体旨在与 ICI 联合给药，作为 FMT 的替代方法，并评估了晚期实体瘤患者的安全性、耐受性和生态反应。
试验达到了主要的安全性和耐受性终点。主要的生态终点没有统计学上的显著差异；然而，随机分组后，MET4 物种相对丰度存在差异，且因患者和物种而异。观察到 MET4 中包括肠球菌和双歧杆菌在内的几个分类群的相对丰度增加，这些分类群先前与 ICI 的反应性有关，并且 MET4 的定植与血浆和粪便中初级胆汁酸的减少有关。
本试验首次报告了在接受 ICI 治疗的晚期癌症患者中，使用微生物联合体替代 FMT 的情况，结果证明进一步开发微生物联合体作为 ICI 治疗癌症的治疗性联合干预措施是合理的。
