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.

项目概要 同种异体造血细胞移植（allo-HCT）通常与已知的临床并发症相关 移植物抗宿主病 (GVHD) 是异基因 HCT 后死亡率的主要驱动因素。目前的方法 GVHD 的预防主要是免疫抑制疗法，可以抑制 GVHD 的预期活性 移植免疫细胞对抗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殖，长期以来一直被认为有助于 GVHD 的病理生理学。事实上，接受异基因 HCT 的患者会受到剧烈的免疫学和 微生物群扰动、HCT 前的发生以及移植期间的持续；之前的胃肠道微生物组多样性 和移植后与临床结果独立相关。当 GVHD 发生时，胃肠道 经常涉及，患者常常死于 GVHD。预防 GVHD 和其他疾病的新方法 迫切需要解决与移植相关的并发症。我们假设恢复肠道健康 HCT 后早期的微生物群落是可行的，并且与改善移植结果和免疫相关 重构。在异基因 HCT 中粪便微生物群移植 (FMT) 的 2 项研究中，我们的小组报告称，FMT 干预是恢复微生物群多样性的安全方法。然而，FMT 具有批次间差异，具体取决于 针对特定的捐赠者，并具有传播传染性生物体或抗生素抗性基因的风险。 在这里，我们提出了一种全新的方法：合理设计的口服生态胶囊，可提供明确的 纯菌株的组成。口服、确定的菌株混合物具有可预测和 药理学可重现，并且可以立即扩展到未来的研究中。在这个多 PI 提案中，我们 将利用正在进行的、研究者发起的多中心安慰剂对照 1b 期试验的样本， 由 PI Doris Ponce 领导，这是第一个在人类中评估克隆衍生的多菌株细菌群落的研究 胃肠道微生物群的预防和恢复 (NCT04995653)。我们组在大型多中心展示 研究表明，早期肠道微生物群失调在各中心普遍发生，并与 移植结果。此外，微生物群失调的创新临床前模型是 转化研究和拟议的微生物组分析。项目目标：与 PI Marcel van den 一起 Brink，评估异基因 HCT 受者肠道微生物群恢复的效果。我们将追求2个具体目标 旨在评估微生物组恢复对胃肠道微生物组、同种异体 HCT 结果的影响，以及 免疫重建。预期结果：结果将为相互作用提供新的机制见解 肠道微生物组和宿主免疫之间的关系。影响：研究结果不仅为未来的研究提供信息 减少移植相关并发症，包括 GVHD，还可以减少胃肠道损伤的其他病症 发生诸如化疗和/或放疗引起的毒性以及非恶性炎症性胃肠道病症。 拟议的项目概述了一个针对 HCT 中胃肠道微生物组的全新框架。