Mechanisms, Prevention and Treatment of Chronic Graft-vs.-Host Disease

慢性移植物抗宿主病的机制、预防和治疗

• 批准号: 8933228
• 负责人: Corey S Cutler
• 金额: $ 168.55万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8933228
• 关键词: Acute Graft Versus Host Disease; Address; Adrenal Cortex Hormones; Allogenic; Antibodies; Antibody Formation; Antigens; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Markers; CSF1R gene; Cell Therapy; Cell physiology; Cellular biology; Chronic; Clinical Research; Clinical Trials; Collagen; Complex; Deposition; Development; Disease; Dose; Elements; Enrollment; Fibrosis; Functional disorder; Future; Goals; Health; Helper-Inducer T-Lymphocyte; Immunoglobulin G; Immunologics; Incidence; Injury; Interleukin-2; Laboratory Study; Lead; Membrane; Modeling; Monitor; Multi-Institutional Clinical Trial; Mus; Newly Diagnosed; Organ; Outcome; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma Cells; Play; Pre-Clinical Model; Prevention; Prophylactic treatment; Research Design; Role; Safety; Series; Signal Pathway; Signal Transduction; Staging; Structure of germinal center of lymph node; Surface; T cell response; Testing; Therapeutic; Therapeutic Agents; Tissues; Transforming Growth Factor beta; Viral; Work; base; chronic graft versus host disease; clinical effect; clinical efficacy; disorder prevention; graft vs leukemia effect; hematopoietic cell transplantation; improved; in vivo; macrophage; monocyte; mortality; mouse model; nanoparticle; novel; novel therapeutics; peptide V; post intervention; pre-clinical; preclinical study; prevent; programs; response; rituximab; transcription factor

DESCRIPTION (provided by applicant): Chronic GVHD (cGVHD) is the most important adverse long-term consequence of allogeneic hematopoietic cell transplantation (HCT) and represents the most frequent cause of mortality occurring after 1-2 years from HCT. In previous studies supported by this Program Project, we made the novel observation that donor B cells played a critical role in the pathophysiology of cGVHD. This was demonstrated in patients with cGVHD as well as in murine models and this led us to undertake a series of clinical trials that demonstrated the clinical efficacy of B cell-directed therapy in the treatment and prevention of cGVHD. The overarching goal of this Program Project in this renewal is to identify optimal strategies for the application of B cell-directed therapies for the treatment and prevention of cGVHD. In this collaborative effort, we incorporate novel pivotal multi-center clinical trials, preclinical models of cGVHD to identify more effective B cell targeting strategies for future clinical studies and detailed analysis of patients receiving novel therapies. This is a highly integrated Program Project where the new clinical trials in Project 1 have been informed by previous pre-clinical murine studies in Project 2 and laboratory studies demonstrating the role of B cells in patients with cGVHD in Project 3. Project 1, Targeting B Cells in Chronic Graft-versus-Host Disease Prevention and Treatment, is dedicated to clinical trials of anti-B cell therapy that address the unmet need during three phases of cGVHD: pre-clinical presentation, initial therapy and late stage disease. These trials are the next phase of studies leading from our prior work, and are informed by the preclinical studies of Project 2. Project 2, Preclinical Drug Approaches to Chronic GVHD Prevention and Treatment is dedicated to the identification and testing of new drug and peptide therapies of cGVHD in a robust mouse model of cGVHD associated with fibrosis. Project 3, Humoral Targets and B Cell Biology in Chronic Graft-vs.-Host Disease is dedicated to understanding the immunologic effects of B cell-directed therapies in patients treated on clinical trials in Project 1, and potential mechanisms by which these new treatments alter B cell function in vivo. Novel discovery in Project 3 may lead to new biomarkers of cGVHD. Supported by unique and highly integrated cores, we have the opportunity to build on our previous discoveries and improve outcomes for patients with cGVHD.

描述（由申请人提供）：慢性GVHD （cGVHD）是同种异体造血细胞移植（HCT）最重要的长期不良后果，是HCT术后1-2年后最常见的死亡原因。在本项目前期支持的研究中，我们观察到供体B细胞在cGVHD的病理生理中起着重要作用。这在cGVHD患者和小鼠模型中都得到了证明，这促使我们进行了一系列临床试验，以证明B细胞导向疗法在治疗和预防cGVHD方面的临床疗效。本次更新项目的总体目标是确定应用B细胞定向疗法治疗和预防cGVHD的最佳策略。在这项合作中，我们结合了新的关键多中心临床试验，cGVHD的临床前模型，以确定更有效的B细胞靶向策略，用于未来的临床研究和接受新疗法的患者的详细分析。这是一个高度整合的项目，项目1的新临床试验是在项目2的临床前小鼠研究和项目3的实验室研究的基础上进行的，这些研究证明了B细胞在cGVHD患者中的作用。项目1：靶向B细胞的慢性移植物抗宿主病预防和治疗，致力于抗B细胞治疗的临床试验，以解决cGVHD临床前表现、初始治疗和晚期疾病三个阶段的未满足需求。这些试验是我们先前工作的下一阶段研究，并由项目2的临床前研究提供信息。项目二，慢性GVHD预防和治疗的临床前药物方法，致力于在cGVHD与纤维化相关的健壮小鼠模型中鉴定和测试cGVHD的新药和肽疗法。项目3：慢性移植物的体液靶点和B细胞生物学。宿主疾病致力于了解B细胞导向疗法在项目1临床试验患者中的免疫作用，以及这些新疗法在体内改变B细胞功能的潜在机制。项目3的新发现可能为cGVHD提供新的生物标志物。在独特和高度集成的核心的支持下，我们有机会在我们之前的发现的基础上，改善cGVHD患者的预后。