Prebiotics to Optimize the Microbiota and Improve Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation

益生元优化微生物群并改善同种异体造血干细胞移植的结果

• 批准号: 10202731
• 负责人: Anthony Sung
• 金额: $ 36.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10202731
• 关键词: Affect; Allogenic; Antibiotic Therapy; Antibiotics; Bacteria; Biological Markers; Blood; Blood Circulation; Blood specimen; Butyrates; Cells; Chemotherapy and/or radiation; Clinical; Clinical Trials; Correlative Study; Data; Disease; Dose; Elements; Energy-Generating Resources; Engraftment; Epithelial Cells; Feces; Fiber; Future; Goals; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Immune system; Infection; Inflammation; Infusion procedures; Intervention; Intestines; Link; Malignant - descriptor; Maximum Tolerated Dose; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Non-Malignant; Oligosaccharides; Outcome; Patients; Phase; Phase I/II Clinical Trial; Phase II Clinical Trials; Placebos; Probiotics; Process; Proteins; Radiation therapy; Randomized; Regulatory T-Lymphocyte; Relapse; Reporting; Role; Safety; Sepsis; Symptoms; T-Cell Development; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation Conditioning; Volatile Fatty Acids; antimicrobial peptide; bacterial community; base; conditioning; design; diagnostic assay; graft vs host disease; gut bacteria; gut colonization; gut health; gut microbiota; immune reconstitution; improved; improved outcome; inflammatory disease of the intestine; interest; islet; leukemia; leukemia/lymphoma; microbiome; microbiota; microbiota transplantation; mortality; peripheral blood; personalized medicine; phase I trial; phase II trial; phase III trial; prebiotics; primary endpoint; response; stem cells; stool sample; systemic inflammatory response

Hematopoietic stem cell transplant (HCT) has the potential to cure leukemia and other malignant and non- malignant diseases. However, these processes are associated with significant morbidity, and treatment-related mortality (TRM) ranges from 10-30%. This is largely due to graft-versus-host disease (GVHD), in which the donor immune system attacks host tissues. GVHD has been linked to disruptions in the bacteria living in the gut (the microbiota), which in turn may be caused by factors such as conditioning chemotherapy, radiation and antibiotic treatment. GVHD and mortality are mediated by the immune system, whose activity in turn is shaped by gut microbiota. Prebiotics are nondigestible fibers that can be safely given to HCT patients and metabolized by existing bacteria in the gut to positively impact bacterial communities and metabolic products such as butyrate. Butyrate is a short chain fatty acid that is an important energy source for colonic epithelial cells and can promote regulatory T cell development, which in turn can modulate GVHD. Our preliminary data suggest that the administration of the prebiotic galacto-oligosaccharide (GOS) to mice undergoing HCT, can both increase butyrate and decrease GVHD. Here we propose the following aims: Aim 1. Evaluate the safety, tolerability, and efficacy of GOS in a phase 1 and randomized phase 2 trial. Aim 1A: We will determine the maximum tolerated dose (MTD) of GOS in a phase 1 dose escalation study (Years 1-2). We hypothesize that GOS is tolerable in doses that increase bacterial diversity and butyrate levels. Aim 1B: We will evaluate the impact of GOS on HCT outcomes in a randomized placebo-controlled phase 2 trial. (Years 2-5). We hypothesize that patients receiving GOS will have better outcomes including decreased grade II-IV GVHD. Aim 1C: We will compare the pre-HCT microbiome of GOS responders (those who received GOS in the phase 1 and phase 2 trials and had increased bacterial diversity) and non-responders (those with no change or decreased bacterial diversity) to determine elements of the pre-HCT microbiome that may be associated with GOS response. Aim 2. Evaluate the impact of GOS on biomarkers of intestinal and systemic inflammation and GVHD as potential mediators of HCT outcomes. The regenerating islet-derived protein 3 alpha (REG3A), is of particular interest. REG3A is an antimicrobial peptide that may be affected by the microbiota and has been reported as a biomarker of GVHD. We hypothesize that patients treated with GOS will have positive changes in biomarkers of inflammation and GVHD (increased REG3A, primary endpoint). As an exploratory aim, biomarkers will be studied for their associated with prebiotic interventions, changes in the microbiome, bacterial metabolites, immune reconstitution, and HCT clinical outcomes (GVHD, TRM, OS). Our long-term goal is to understand how prebiotic interventions impact the microbiota and bacterial metabolites and use prebiotics to decrease inflammation and improve HCT outcomes. We expect that the data generated from this study will lead to future clinical trials, including a multicenter randomized phase 3 trials, or to microbiota-based diagnostic assays to personalize therapies.

造血干细胞移植（HCT）具有治愈白血病和其他恶性和非恶性肿瘤的潜力。 恶性疾病然而，这些过程与显著的发病率和治疗相关性相关。 死亡率（TRM）为10- 30%。这主要是由于移植物抗宿主病（GVHD），其中供体 免疫系统攻击宿主组织。移植物抗宿主病与肠道细菌的破坏有关（ 微生物群），这反过来又可能是由条件化疗、放疗和抗生素等因素引起的 治疗GVHD和死亡率是由免疫系统介导的，而免疫系统的活动反过来又由肠道决定。 微生物群益生元是不易消化的纤维，可以安全地给予HCT患者，并通过 肠道中现有的细菌，以积极影响细菌群落和代谢产物，如丁酸盐。 丁酸是一种短链脂肪酸，是结肠上皮细胞的重要能量来源， 调节性T细胞发育，这反过来又可以调节GVHD。我们的初步数据表明， 对进行HCT的小鼠施用益生元低聚半乳糖（GOS）， 降低GVHD。在此，我们提出以下目标：目标1。评估安全性、耐受性和 GOS在1期和随机2期试验中的疗效。目标1A：我们将确定最大耐受量 在1期剂量递增研究（第1-2年）中，GOS的最大耐受剂量（MTD）。我们假设GOS是可以容忍的， 增加细菌多样性和丁酸水平的剂量。目的1B：我们将评估GOS对HCT的影响 随机安慰剂对照2期试验的结果。（2-5年级）。我们假设， GOS将有更好的结局，包括减少II-IV级GVHD。目标1C：我们将比较前HCT GOS应答者的微生物组（在1期和2期试验中接受GOS治疗并增加了 细菌多样性）和无应答者（细菌多样性无变化或减少的那些），以确定 可能与GOS反应相关的前HCT微生物组的元素。目标二。评估的影响 GOS对肠道和全身炎症生物标志物的影响以及GVHD作为HCT的潜在介质 结果。再生胰岛衍生蛋白3 α（REG 3A）是特别感兴趣的。REG 3A是一个 抗微生物肽可能受到微生物群的影响，并已被报道为GVHD的生物标志物。 我们假设接受GOS治疗的患者在炎症生物标志物方面会有积极的变化， GVHD（REG 3A增加，主要终点）。作为探索性目标，将研究生物标志物的 与益生元干预、微生物组变化、细菌代谢物、免疫重建 和HCT临床结果（GVHD、TRM、OS）。我们的长期目标是了解益生元干预是如何 影响微生物群和细菌代谢产物，并使用益生元来减少炎症和改善HCT 成果。我们预计，这项研究产生的数据将导致未来的临床试验，包括 多中心随机3期试验，或基于微生物的诊断测定，以个性化治疗。