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，也是 HCT 1-2 年后最常见的死亡原因。在该项目支持的先前研究中，我们发现供体 B 细胞在 cGVHD 的病理生理学中发挥着关键作用。这在 cGVHD 患者以及小鼠模型中得到了证明，这促使我们开展了一系列临床试验，证明 B 细胞定向疗法在治疗和预防 cGVHD 方面的临床疗效。本次更新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，我们结合了新颖的关键多中心临床试验、cGVHD 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。这是一个高度综合的项目，项目 1 中的新临床试验是根据项目 2 中先前的临床前小鼠研究和项目 3 中证明 B 细胞在 cGVHD 患者中的作用的实验室研究提供的信息。项目 1，靶向 B慢性移植物抗宿主病预防和治疗中的细胞致力于抗 B 细胞疗法的临床试验，以解决 cGVHD 三个阶段中未满足的需求：临床前表现、初始治疗和晚期疾病。这些试验是我们之前工作的下一阶段研究，并以项目 2 的临床前研究为基础。项目 2，慢性 GVHD 预防和治疗的临床前药物方法致力于新药和肽疗法的鉴定和测试与纤维化相关的 cGVHD 稳健小鼠模型中的 cGVHD 的研究。项目 3，慢性移植物抗宿主病中的体液靶标和 B 细胞生物学，致力于了解 B 细胞定向疗法对项目 1 临床试验中治疗的患者的免疫学影响，以及这些新疗法改变的潜在机制B细胞在体内发挥功能。项目 3 中的新发现可能会产生新的 cGVHD 生物标志物。在独特且高度集成的核心的支持下，我们有机会在我们之前的发现的基础上再接再厉，改善 cGVHD 患者的治疗结果。