A prospective evaluation of the gut microbiome as a mediator of lymphoma treatment outcome and systemic immunity

肠道微生物组作为淋巴瘤治疗结果和全身免疫调节因子的前瞻性评估

• 批准号: 10419202
• 负责人: Catherine Sibyl Diefenbach
• 金额: $ 71.79万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-24 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419202
• 关键词: Adriamycin PFS; Antibiotics; B-Cell Lymphomas; B-Lymphocytes; Behavior; Biological; Blood; Blood specimen; CD14 gene; Cells; Chronic; Chronology; Clinical; Communities; Cyclophosphamide; Data; Detection; Development; Diagnosis; Diet; Disease-Free Survival; Etiology; Evaluation; Failure; Family; Feces; Functional Imaging; Future; Goals; Growth; Hodgkin Disease; Homeostasis; Host Defense; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immuno-Chemotherapy; Immunotherapy; Inferior; Intervention; Investigation; Lead; Link; Lipopolysaccharides; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mathematics; Measurement; Mediator of activation protein; Medical; Metagenomics; Methodology; Methods; Microbe; Mus; Myeloid Cells; Natural Immunity; Organism; Outcome; PET/CT scan; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Play; Population; Prednisone; Research; Role; Sampling; Shotgun Sequencing; Solid Neoplasm; Structure; Supportive care; T memory cell; T-Lymphocyte; Taxon; Testing; Therapeutic; Time Series Analysis; Transcript; Treatment Failure; Treatment outcome; Vincristine; Work; adaptive immunity; anti-tumor immune response; antigen-specific T cells; base; clinical care; cytokine; dietary; experimental study; fecal transplantation; follow-up; gut bacteria; gut microbiome; gut microbiota; immune activation; immunoregulation; improved; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; lipopolysaccharide-binding protein; microbial; microbial composition; microbiome signature; microbiota; microbiota profiles; neoplastic cell; novel; personalized therapeutic; probiotic therapy; prospective; protein biomarkers; responders and non-responders; response; rituximab; stool sample; targeted treatment; temporal measurement; therapy outcome; treatment duration; treatment response

ABSTRACT/SUMMARY Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a significant clinical problem, with only 60% of patients cured. Mechanisms for how DLBCL, an immune cancer, evades host defenses are poorly understood. Growing evidence suggests that the human gut microbiota (GMB) plays important roles in regulating innate and adaptive immunity, and is associated with therapeutic outcome in multiple solid tumor types. Based on this connection, we hypothesize that the GMB influences lymphoma behavior by altering the anti-tumor immune response. Our preliminary data provide compelling evidence that DLBCL patients: a) have distinct GMB compositions in which many commensal families are lost; and b) show chronic activation in central and effector memory T cells. However, the connections between GMB and lymphoma remain poorly understood, limiting the development of targeted therapies. The overall goal of the proposed research is to investigate longitudinally the impact of GMB signatures on clinical response and systemic immunity in DLBCL. Thus, our specific aims are: Aim 1: To investigate in untreated DLBCL the association between the GMB and treatment response using 16S and full metagenomic shotgun sequencing of stool samples from 300 patients pre-treatment, during treatment, and at 12 months, a validated endpoint for clinical outcome; Aim 2: To evaluate the potential bi-directional associations between GMB and DLBCL by tracking concurrent stool and weekly blood samples which we will analyze with novel Bayesian timeseries methods for a subset of 50 DLBCL patients daily during the first 14 days of treatment, and then in follow-up as in Aim 1; Aim 3: To investigate functional relationships between immune activation and microbial diversity, including translocation of microbial products from the gut into the blood and expansion of antigen-specific T cells directed against poor outcome microbes. The scientific premise is supported by extensive pilot data and rigorous application of established methods. The proposed study is highly innovative, as it will be the first large scale longitudinal and prospective investigation of the GMB in lymphoma, using state of the art methodologies such as, full metagenomic shotgun sequencing, AbSeq, and Bayesian time series analysis. This research has the potential to significantly advance lymphoma research by identifying the GMB and systemic immune pathways that impact treatment failure in DLBCL, and it may provide the biologic insights for new personalized therapeutics. We will build on our findings to develop personalized microbial-based therapies, which could range from dietary changes that would favor growth of organisms we demonstrate to be beneficial, to targeted probiotic therapy and/or fecal transplantation to reduce microbes we show are deleterious. Because gut bacteria are modifiable, our findings could lead in the future to the implementation of tailored microbial-based therapies, a new and minimally toxic treatment paradigm for DLBCL patients, a significant unmet medical need.

摘要/总结 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤，是一个重要的临床问题， 60%的患者治愈。DLBCL是一种免疫性癌症，如何逃避宿主防御的机制很差 明白越来越多的证据表明，人类肠道微生物群（GMB）在调节 先天性和适应性免疫，并与多种实体瘤类型的治疗结果相关。基于 关于这一点，我们假设GMB通过改变淋巴瘤细胞的抗肿瘤活性来影响淋巴瘤的行为。 免疫反应我们的初步数据提供了令人信服的证据，DLBCL患者：a）具有明显的 GMB组合物，其中许多神经系统家族丢失;和B）在中枢和中枢神经系统中显示慢性激活， 效应记忆T细胞然而，GMB和淋巴瘤之间的联系仍然知之甚少， 限制了靶向治疗的发展。本研究的总体目标是调查 纵向研究GMB特征对DLBCL临床应答和全身免疫的影响。 因此，我们的具体目标是：目的1：研究在未经治疗的DLBCL中GMB与DLBCL之间的关联。 使用来自300名患者的粪便样品的16 S和全宏基因组鸟枪测序的治疗反应 治疗前、治疗期间和12个月时，临床结局的经验证终点;目的2：评价 通过跟踪同时排便和每周血液，确定GMB和DLBCL之间的潜在双向关联 我们将用新的贝叶斯时间序列方法分析每天50例DLBCL患者的亚组样本 在治疗的前14天，然后在目标1中的随访中;目标3：研究功能性 免疫激活和微生物多样性之间的关系，包括微生物产物的易位 从肠道进入血液和抗原特异性T细胞的扩增针对不良结果的微生物。 科学前提得到了广泛的试点数据和严格应用既定方法的支持。 这项研究具有很强的创新性，因为它将是第一个大规模的纵向和前瞻性研究。 淋巴瘤中GMB的研究，使用最先进的方法，如全宏基因组鸟枪法 测序、AbSeq和贝叶斯时间序列分析。这项研究有可能大大推进 淋巴瘤研究通过确定GMB和全身免疫途径，影响治疗失败， DLBCL，它可能为新的个性化治疗提供生物学见解。我们会在调查结果的基础上 开发个性化的基于微生物的疗法，包括改变饮食， 我们证明有益的生物体的生长，靶向益生菌治疗和/或粪便移植， 减少我们发现的有害微生物因为肠道细菌是可以改变的，我们的发现可能会导致 未来的实施量身定制的微生物为基础的治疗，一个新的和最低毒性的治疗模式 对于DLBCL患者，这是一个显著未满足的医疗需求。