Intestinal microbiome restoration in allogeneic stem cell transplantation

同种异体干细胞移植中的肠道微生物组恢复

• 批准号: 10660334
• 负责人: Doris Ponce
• 金额: $ 44.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660334
• 关键词: Allogenic; Antibiotic Resistance; Bacteria; Cells; Cessation of life; Chemotherapy and/or radiation; Clinical; Complication; Data; Ecosystem; Enterococcus; Functional disorder; Funding; Future; Gastrointestinal Injury; Gastrointestinal tract structure; Health; Hematocrit procedure; Hematologic Neoplasms; Immune; Immune system; Immunity; Immunologics; Infection; Infectious Agent; Inflammatory; Intervention; Intestines; Knowledge; Malignant Neoplasms; Multicenter Studies; Mus; Non-Malignant; Oral; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Pharmacology; Phase; Phase Ib Trial; Placebo Control; Population; Pre-Clinical Model; Prevention; Production; Prophylactic treatment; Reporting; Reproducibility; Research Personnel; Risk; Sampling; Stem cell transplant; Therapeutic immunosuppression; Tissues; Toxic effect; Transplant Recipients; Transplantation; Treatment Protocols; Volatile Fatty Acids; capsule; curative treatments; dysbiosis; fecal transplantation; first-in-human; gastrointestinal; gastrointestinal function; graft vs host disease; gut microbiome; gut microbiota; hematopoietic cell transplantation; human study; immune reconstitution; improved; innovation; insight; member; metabolomics; microbial colonization; microbial community; microbiome; microbiome analysis; microbiota; mortality; novel; novel strategies; pathobiont; phase 3 study; placebo controlled trial; post-transplant; preservation; prevent; prospective; rational design; reconstitution; resistance gene; restoration; scale up; therapeutic evaluation; translational study; transmission process; transplant centers; tumor

PROJECT SUMMARY Allogeneic hematopoietic cell transplantation (allo-HCT) is often associated with a clinical complication known as graft-versus-host disease (GVHD), a major driver of mortality after allo-HCT. Current approaches to the prophylaxis of GVHD are primarily immunosuppressive therapies that can dampen the intended activity of the transplanted immune cells against the tumor and cause delayed immune reconstitution. Gastrointestinal (GI) microbiota, the highest microbial colonization in the body, has long been understood to contribute to the pathophysiology of GVHD. Indeed, patients undergoing allo-HCT are subject to dramatic immunological and microbiota perturbations, developing pre-HCT and continuing during transplant; GI microbiome diversity before and after transplant are independently associated with clinical outcome. When GVHD occurs, the GI tract is frequently involved, and patients often succumb to GVHD. New approaches to prevent GVHD and other transplant-related complications are urgently needed. We hypothesize that restoring the health of the intestinal microbial community early post-HCT is feasible and associated with improved transplant outcomes and immune reconstitution. In 2 studies of fecal microbiota transplantation (FMT) in allo-HCT, our group reported that an FMT intervention is a safe way to restore microbiota diversity. However, FMT has batch-to-batch variability depending on specific donors and carries the risks of transmission of infectious organisms or antibiotic-resistance genes. Here, we propose an entirely novel approach: a rationally designed oral-ecobiotic capsule that delivers a defined composition of pure bacterial strains. An oral, defined blend of strains offers advantages of predictable and reproducible pharmacology and would be immediately scalable to future studies. On this multi-PI proposal, we will capitalize on samples from an ongoing, investigator-initiated multicenter placebo-controlled phase 1b trial, led by PI Doris Ponce, which is first-in-human evaluating a clonally-derived multi-strain bacterial consortia for the prevention and restoration of the GI microbiome (NCT04995653). Our group has shown in a large multicenter study that early intestinal microbiome dysbiosis occurred universally among centers and had an association with transplant outcomes. In addition, innovative preclinical models of microbiome dysbiosis serve as the basis for the translational study and proposed microbiome analyses. Project objectives: Along with PI Marcel van den Brink, to evaluate the effects of intestinal microbiota restoration in allo-HCT recipients. We will pursue 2 specific aims that will evaluate the effects of microbiome restoration in the GI microbiome, allo-HCT outcomes, and immune reconstitution. Expected outcome: Results will provide new mechanistic insights into interactions between the intestinal microbiome and host immunity. Impact: Findings will inform future research not only for the reduction of transplant-related complications including GVHD, but also for other conditions in which GI injury occurs such as chemotherapy and/or radiation-induced toxicity and non-malignant inflammatory GI conditions. The proposed project outlines an entirely novel framework for targeting the GI microbiome in HCT.

项目摘要 同种异体造血细胞移植（Allo-HCT）通常与已知的临床并发症有关 作为移植物抗宿主病（GVHD），这是Allo-HCT后死亡率的主要驱动力。当前的方法 GVHD的预防主要是免疫抑制疗法，可以抑制预期活性 移植的免疫细胞针对肿瘤，并导致免疫重建延迟。胃肠道（GI） 微生物群是体内最高的微生物定植，长期以来一直被认为有助于 GVHD的病理生理。实际上，接受异hct的患者受到戏剧性的免疫学和 菌群扰动，在移植期间发展并持续发展； GI微生物组多样性之前 在移植后与临床结果独立相关。当GVHD发生时，胃肠道是 经常参与，患者经常屈服于GVHD。预防GVHD和其他的新方法 迫切需要与移植相关的并发症。我们假设恢复肠道的健康 微生物社区早期HCT是可行的，并且与改善的移植结局和免疫力有关 重组。在两项在Allo-HCT中的粪便菌群移植（FMT）的研究中，我们的小组报告说FMT 干预是恢复微生物群多样性的安全方法。但是，FMT具有批处理变异性 在特定的供体上，具有传染性生物或抗生素抗性基因的传播风险。 在这里，我们提出了一种完全新颖的方法：一种理性设计的口腔生物胶囊，可提供定义的 纯细菌菌株的组成。口服，定义的菌株混合物提供了可预测和的优势 可重复的药理学，将立即对未来的研究进行扩展。关于这个多PI的建议，我们 将利用正在进行的，调查员发动的多中心安慰剂对照的1B期试验中的样本， 由Pi Doris ponce领导，该ponce是首次人类评估克隆衍生的多晶体细菌联盟 GI微生物组的预防和恢复（NCT04995653）。我们的小组在一个大型的多中心中显示 研究表明，早期肠道微生物组营养不良发生在中心之间，并与 移植结果。此外，微生物组营养不良的创新临床前模型是 翻译研究和提出的微生物组分析。项目目标：与Pi Marcel Van Den一起 边缘，以评估肠道菌群恢复对异晶型HCT受体的影响。我们将追求2个特定的 将评估微生物组恢复在GI微生物组，Allo-HCT结果和 免疫重建。预期结果：结果将为互动提供新的机械见解 在肠道微生物组和宿主免疫之间。影响：调查结果不仅会为未来的研究提供信息 减少了包括GVHD在内的移植相关并发症，但也针对GI损伤的其他条件 发生的发生，例如化学疗法和/或辐射诱导的毒性和非恶性炎症性GI条件。 拟议的项目概述了针对HCT中GI微生物组的完全新颖的框架。