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: 9337365
• 负责人: Corey S Cutler
• 金额: $ 163.04万
• 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/9337365
• 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; Critical Pathways; Deposition; Development; Disease; Dose; Elements; Enrollment; Fibrosis; Functional disorder; Future; Goals; Helper-Inducer T-Lymphocyte; Immunoglobulin G; Immunologics; Incidence; Injury; Interleukin-2; Laboratory Study; Lead; Membrane; Monitor; Multi-Institutional Clinical Trial; Mus; Newly Diagnosed; Organ; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Phase; Plasma Cells; Play; Pre-Clinical Model; Prevention; Prophylactic treatment; Research Design; Role; Safety; Series; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Surface; T cell response; Testing; Therapeutic; Therapeutic Agents; Tissues; Transforming Growth Factor beta; Viral; Work; autoreactivity; base; biomarker development; chronic graft versus host disease; clinical effect; clinical efficacy; disorder prevention; graft vs leukemia effect; hematopoietic cell transplantation; improved; improved outcome; in vivo; macrophage; monocyte; mortality; mouse model; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; peptide V; post intervention; pre-clinical; preclinical study; prevent; programs; public health relevance; response; rituximab; survival outcome; 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）的最重要的不良长期后果，是HCT 1 - 2年后发生的最常见死亡率的原因。在该计划项目支持的先前研究中，我们对供体B细胞在CGVHD的病理生理中起着至关重要的作用进行了新的观察。这在CGVHD和鼠模型的患者中证明了这一点，这使我们进行了一系列临床试验，这些试验证明了B细胞指导疗法在治疗和预防CGVHD方面具有临床功效。该计划项目在此续签中的总体目标是确定用于应用B细胞指导疗法以治疗和预防CGVHD的最佳策略。在这项协作工作中，我们结合了新型的关键多中心临床试验，即CGVHD的临床前模型，以确定对未来临床研究的更有效的B细胞靶向策略，并对接受新疗法的患者进行了详细的分析。这是一个高度综合的计划项目，在项目2中先前的临床前鼠研究和实验室研究中，项目1中的新临床试验已经告知了B细胞在项目3中的CGVHD患者中的作用。项目1。项目1，靶向B细胞在慢性移植物抗宿主疾病预防和治疗中的b细胞在临床疗法的临床试验中，以解决抗临床疗法的临床试验：表现，初始治疗和晚期疾病。这些试验是从我们先前的工作中引导的下一个研究的下一阶段，并且由项目2的临床前研究所告知，临床前的药物预防和治疗方法专门用于鉴定和测试与纤维化相关的CGGVHD鲁棒小鼠模型中CGVHD的新药物和肽疗法。项目3，慢性移植物中的体液靶标和B细胞生物学，宿主疾病致力于理解B细胞指导疗法在项目1中接受临床试验治疗的患者中的免疫学作用，以及这些新疗法的潜在机制改变了VIVO中B细胞功能的潜在机制。项目3中的新发现可能导致CGVHD的新生物标志物。在独特且高度集成的核心的支持下，我们有机会建立以前的发现并改善CGVHD患者的结果。