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.

抽象的 肠道微生物群由多种微生物组成，对人类有多种影响 （病理）生理学。微生物组的组成与许多疾病有关，但因果推断是 经常缺乏。临床前和临床研究表明，肠道菌群可以调节先天性 以及适应性免疫，包括异体造血细胞后的T细胞和抗肿瘤免疫 移植（allo-HCT）和检查点封锁。我的实验室重点研究肠道微生物群在 同种异体 HCT 和免疫治疗的结果。例如，我们表明微生物群的组成经历了 allo-HCT 期间发生显着且频繁的变化，并且较低的肠道微生物群多样性与 死亡率增加。我们还发现，某些物种（最常见的是肠球菌）占主导地位 与致命的移植物抗宿主病（GVHD）有关；接触某些抗生素与 同种异体 HCT 和嵌合抗原受体 T 细胞 (CART) 治疗后结果更差；还有那个造血 重建与有益菌群的存在有关。这些研究已转化为临床 使用自体粪便微生物群移植、特定细菌群的施用和抗生素的试验 管理以保护和/或恢复共生菌群。该提案的总体假设是 肠道微生物群是癌症环境中先天性和适应性免疫的重要调节剂 免疫疗法。虽然免疫疗法对某些接受者有疗效，但可以提高其疗效并减少 毒性是肿瘤学中未满足的需求。主要目标是通过靶向改善癌症免疫治疗 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中的研究的例子 包括：a) 开发用于微生物组分析的新管道，b) 相关的临床前和临床项目 肠道微生物组和 CART，c) 分析饮食和药物对肠道影响的新技术 微生物组，以及 d) 有关胆汁酸免疫调节的临床前和临床研究，例如 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） 来自该应用程序）以及一种新颖的多组学方法来整合患者、微生物组和肿瘤分析 使用计算平台（MSK-MIND）进行数据协调和机器学习的模式。这些 调查将通过小鼠和人类之间的永久对话进行：人类研究 使我们能够观察相关性、提出假设并测试治疗策略；动物研究使 我们建立或反驳微生物群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，以测试治疗策略以增强 在接受癌症免疫治疗（例如 CART 和 allo-HCT）的患者中发挥疗效并降低毒性。