The role of the intestinal microbiome in cancer immunotherapy

肠道微生物组在癌症免疫治疗中的作用

• 批准号: 10738072
• 负责人: Marcel R M van den Brink
• 金额: $ 106.2万
• 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: 2023-08-01 至 2030-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738072
• 关键词: Abate; Allogenic; Animals; Antibiotics; Autologous; Bile Acids; CAR T cell therapy; Clinical; Clinical Research; Clinical Trials; Communities; Data; Development; Diet; Disease; Enterococcus; Exposure to; Funding; Future; Goals; Hematopoietic; Human; Immunity; Immunology; Immunotherapy; Investigation; Machine Learning; Malignant Neoplasms; Microbe; Modality; Mus; Natural Immunity; Oncology; Outcome; Patients; Pharmaceutical Preparations; Physiology; Research; Role; Sampling; T-Lymphocyte; Techniques; Toxic effect; Translating; Tumor Immunity; Work; adaptive immunity; beneficial microorganism; cancer immunotherapy; chimeric antigen receptor T cells; clinical development; commensal microbes; computational platform; data harmonization; fecal transplantation; graft vs host disease; gut microbiome; gut microbiota; hematopoietic cell transplantation; immune checkpoint blockade; immunoregulation; improved; insight; microbiome; microbiome analysis; microbiome composition; microbiota; mortality; multiple omics; novel; pre-clinical; preclinical study; reconstitution; therapeutic evaluation; tumor

ABSTRACT The gut microbiota consists of a community of diverse microbes and has many effects on human (patho)physiology. Microbiome composition has been associated with many diseases, but causal inference is often lacking. Preclinical and clinical studies have demonstrated that the intestinal microbiota can regulate innate and adaptive immunity, including T cell and antitumor immunity after allogeneic hematopoietic cell transplantation (allo-HCT) and checkpoint blockade. My lab has focused on the role of gut microbiota in outcomes of allo-HCT and immunotherapy. For example, we showed that microbiota composition undergoes significant and frequent changes during allo-HCT and that lower intestinal microbiota diversity is associated with increased mortality. We also found that dominance by certain species, most frequently Enterococcus, is associated with lethal graft-versus-host disease (GVHD); that exposure to certain antibiotics is associated with worse outcomes following allo-HCT and chimeric antigen receptor T cell (CART) therapy; and that hematopoietic reconstitution is associated with the presence of beneficial flora. These studies have been translated into clinical trials using autologous fecal microbiota transplant, administration of defined bacterial consortia, and antibiotic stewardship to spare and/or restore the commensal flora. The overarching hypothesis of this proposal is that the intestinal microbiome is an important modulator of innate and adaptive immunity in the setting of cancer immunotherapy. While immunotherapies are curative in some recipients, improving their efficacy and abating toxicities are unmet needs in oncology. The major goals are to improve cancer immunotherapy by targeting the intestinal microbiome based on preclinical and clinical studies. Examples of our ongoing and planned studies include: a) development of a new pipeline for microbiome analysis, b) preclinical and clinical projects regarding intestinal microbiome and CART, c) new techniques to analyze the effects of diet and drugs on the intestinal microbiome, and d) preclinical and clinical studies regarding immune modulation by bile acids, as an example how we study the mechanisms by which the intestinal microbiome can modulate immunity and cancer immunotherapy. We have organized a multicenter global consortium to collect fecal samples (funded separately from this application) along with a novel multi-omic approach to integrate patient, microbiome, and tumor profiling modalities using a computational platform (MSK-MIND) for data harmonization and machine learning. These investigations will be performed via perpetual dialogue between work with mice and humans: human studies enable us to observe correlations, develop hypotheses, and test therapeutic strategies; animal studies enable us to establish or refute causal relationships between microbiota and host immunology and to obtain mechanistic insights. These data will inform the future development of clinical trials to test therapeutic strategies to enhance efficacy and decrease toxicity in patients receiving cancer immunotherapy, such as CART and allo-HCT.

摘要 肠道菌群由多种微生物组成，对人体有多种影响 （病理）生理学。微生物组组成与许多疾病有关，但因果推断是 往往缺乏。临床前和临床研究表明，肠道微生物群可以调节先天性 获得性免疫，包括异基因造血细胞移植后的T细胞免疫和抗肿瘤免疫 移植（allo-HCT）和检查点阻断。我的实验室专注于肠道微生物群在 allo-HCT和免疫治疗的结果。例如，我们发现微生物群的组成经历了 allo-HCT期间显著和频繁的变化以及较低的肠道微生物群多样性与 增加死亡率。我们还发现，某些物种的优势，最常见的是肠球菌， 与致命的移植物抗宿主病（GVHD）相关;暴露于某些抗生素与 allo-HCT和嵌合抗原受体T细胞（CART）治疗后的结局更差; 重建与有益植物群的存在有关。这些研究已经转化为临床 使用自体粪便微生物群移植、施用确定的细菌聚生体和抗生素的试验 保护和/或恢复植物植物群。这一建议的首要假设是， 肠道微生物组是癌症背景下先天和适应性免疫的重要调节剂 免疫疗法虽然免疫疗法在一些接受者中是治愈性的，但提高其疗效并减轻其不良反应， 毒性是肿瘤学中未满足的需求。主要目标是通过靶向肿瘤细胞来改善癌症免疫治疗。 基于临床前和临床研究的肠道微生物组。我们正在进行和计划进行的研究的例子 包括：a）开发用于微生物组分析新管道，B）临床前和临床项目， 肠道微生物组和CART，c）分析饮食和药物对肠道微生物的影响的新技术， 微生物组，和d）关于胆汁酸的免疫调节的临床前和临床研究，作为实例 我们如何研究肠道微生物组调节免疫和癌症的机制 免疫疗法。我们组织了一个多中心的全球联盟来收集粪便样本（单独资助 沿着一种新的多组学方法来整合患者、微生物组和肿瘤谱 使用计算平台（MSK-MIND）进行数据协调和机器学习。这些 研究将通过小鼠和人类工作之间的永久对话进行：人类研究 使我们能够观察相关性，发展假设，并测试治疗策略;动物研究使 我们建立或反驳微生物与宿主免疫学之间的因果关系，并获得机制 见解.这些数据将为临床试验的未来发展提供信息，以测试治疗策略， 在接受癌症免疫疗法如CART和allo-HCT的患者中，