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/摘要 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤，是一个重大的临床问题，只有 60％的患者治愈。 DLBCL（免疫癌）逃避宿主防御的机制很差 理解。越来越多的证据表明，人类肠道菌群（GMB）在调节中起着重要作用 先天和适应性免疫，并且与多种实体瘤类型的治疗结果有关。基于 在这方面，我们假设GMB通过改变抗肿瘤来影响淋巴瘤行为 免疫反应。我们的初步数据提供了令人信服的证据，表明DLBCL患者：a） GMB的组成，其中许多共生家庭丢失了； b）在中央和 效应器记忆T细胞。但是，GMB和淋巴瘤之间的连接仍然很少了解， 限制靶向疗法的发展。拟议研究的总体目标是调查 纵向GMB特征对DLBCL的临床反应和全身免疫力的影响。 因此，我们的具体目的是：目标1：在未处理的DLBCL中调查GMB与 使用300例患者的粪便样品的16S和完全元基因组shot弹枪测序的治疗反应 预处理，在治疗期间，在12个月时，是临床结局的经过验证的终点；目标2：评估 通过跟踪并发粪便和每周的血液，GMB和DLBCL之间的潜在双向关联 我们将使用新颖的贝叶斯时间工程方法分析的样品，每天为50个DLBCL患者的子集进行分析 在治疗的前14天，然后在AIM 1中进行随访；目标3：调查功能 免疫激活与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，并针对不良结果微生物的抗原特异性T细胞的膨胀。 科学的前提得到了广泛的试点数据和既定方法的严格应用。 拟议的研究具有很高的创新性，因为它将是第一个大规模的纵向和前瞻性 使用艺术方法（例如，全元基因组shot弹枪）对淋巴瘤中GMB的研究 测序，ABSEQ和贝叶斯时间序列分析。这项研究有可能大大提高 淋巴瘤研究通过确定影响治疗失败的GMB和全身免疫途径 DLBCL，它可以为新的个性化治疗剂提供生物学见解。我们将基于我们的发现 开发基于微生物的个性化疗法，这可能从有希望的饮食变化范围 生物的生长我们证明是有益的，对有针对性的益生菌治疗和/或粪便移植到 减少我们显示的微生物是有害的。因为肠道细菌是可修改的，所以我们的发现可能会导致 未来实施量身定制的基于微生物的疗法，这是一种新的且微不足道的治疗范式 对于DLBCL患者，医疗需求很大。