Project 1: Targeting B Cells in Chronic Graft-vs.Host Disease Prevention and Treatment

项目1：靶向B细胞预防和治疗慢性移植物抗宿主病

• 批准号: 8933234
• 负责人: Corey S Cutler
• 金额: $ 25.75万
• 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/8933234
• 关键词: Acute Graft Versus Host Disease; Address; Adrenal Cortex Hormones; Alloantigen; Allogenic; Antibodies; B-Lymphocytes; Biological; Biology; Cell Therapy; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Complex; Development; Disease; Dose; Drug Targeting; Elements; Functional disorder; Funding; Future; Generations; Grant; H-Y Antigen; Human; Immunologic Monitoring; Immunologics; Incidence; Interleukin-2; Investigation; Isoantibodies; Laboratories; Monoclonal Antibodies; Morbidity - disease rate; Newly Diagnosed; Outcome; Pathway interactions; Patients; Phase; Phase I/II Trial; Placebos; Prevention; Prophylactic treatment; Quality of life; Randomized; Receptors, Antigen, B-Cell; Refractory; Regulatory T-Lymphocyte; Relapse; Research Personnel; Risk; Role; Safety; Sampling; Series; Serological; Severities; Signal Pathway; Staging; Stem cell transplant; Steroids; Testing; Therapeutic; abstracting; arm; chronic graft versus host disease; clinical effect; data management; disorder prevention; hematopoietic cell transplantation; inhibitor/antagonist; mortality; mouse model; novel; phase 2 study; phase I trial; phase II trial; pre-clinical; preclinical study; prevent; programs; prophylactic; reconstitution; repository; response; rituximab; trafficking; trial comparing

Project Summary/Abstract Project 1 Chronic GVHD (cGVHD) is the most important adverse long-term consequence of allogeneic hematopoietic cell transplantation (HCT). Responsible for the majority of mortality occurring after 1-2 years from HCT, cGVHD is also an important cause of chronic morbidity and diminished quality of life after HCT. The overarching theme of this proposal is to study the role of the B cell in the pathophysiology of cGVHD, and Project 1 is dedicated to clinical trials that specifically target the B cell compartment for the prevention and treatment of cGVHD. In Specific Aim 1, we target preclinical cGVHD with a prophylactic strategy aiming to deplete B cells as they reconstitute early after HCT. In a phase II study conducted in the prior funding period, we addressed the hypothesis that the early post-HCT administration of the monoclonal antibody, rituximab, would reduce the incidence and severity of cGVHD, allowing markedly less systemic corticosteroid use. While effective, prevention was incomplete, so we now plan a multicenter, randomized phase II trial of B cell depletion as a preventative strategy against cGVHD using a novel second generation antibody. Recognizing that B cells alone cannot be solely responsible for the occurrence of cGVHD, we combine the strategy of B cell depletion using rituximab with regulatory T cell (TREG) enhancement using low-dose IL-2 in Specific Aim 2. In the prior funding period, we were able to demonstrate that IL-2 was able to increase the number of circulating TREG cells and this was correlated with clinical response in established steroid-refractory cGVHD. In this project we explore the utility of this two-pronged approach in patients with newly diagnosed cGVHD in an attempt to more effectively treat cGVHD and prevent the long-term sequelae of cGVHD. Specific Aim 3 will examine a series of promising compounds for the treatment of advanced cGVHD, all of which target B cells, either through the B cell receptor or through related signaling pathways. In the later years of the grant compounds with activity will be applied earlier in the development of cGVHD. The clinical studies we propose in Project 1 are intimately interlocked with the other Projects and Cores in this Program. In Project 1 we extend the basic biological discoveries of Project 3 and pre-clinical studies of Project 2 into the clinical setting.

项目概要/摘要项目1 慢性GVHD（cGVHD）是同种异体造血干细胞移植最重要的长期不良后果， 细胞移植（HCT）。导致HCT后1-2年发生的大多数死亡， cGVHD也是HCT后慢性发病和生活质量下降的重要原因。的 该提案的首要主题是研究B细胞在cGVHD病理生理学中的作用， 项目1致力于专门针对B细胞隔室的临床试验， cGVHD的治疗在具体目标1中，我们针对临床前cGVHD的预防策略，旨在 在HCT后早期重建时耗尽B细胞。在前一个资助期进行的第二阶段研究中， 我们提出了这样的假设，即HCT后早期给予单克隆抗体，利妥昔单抗， 将降低cGVHD的发生率和严重程度，允许显著减少全身性皮质类固醇的使用。而 有效，预防是不完全，所以我们现在计划一个多中心，随机的第二阶段试验的B细胞 使用新的第二代抗体，作为针对cGVHD的预防性策略。认识 B细胞不能单独导致cGVHD的发生，我们联合收割机B细胞的策略， 在特异性Aim 2中使用利妥昔单抗的消耗与使用低剂量IL-2的调节性T细胞（TREG）增强。在 在前一个资助期，我们能够证明IL-2能够增加循环的数量， Treg细胞，这与已建立的类固醇难治性cGVHD的临床反应相关。在这个项目中 我们探索这种双管齐下的方法在新诊断的cGVHD患者中的效用， 更有效地治疗cGVHD并预防cGVHD的长期后遗症。具体目标3将审查 一系列有前途的化合物用于治疗晚期cGVHD，所有这些化合物都靶向B细胞， 通过B细胞受体或通过相关的信号传导途径。在格兰特化合物的后期 将在cGVHD的开发中更早地应用。我们在项目1中提出的临床研究 与本计划中的其他项目和核心密切相关。在项目1中，我们扩展了 项目3的生物学发现和项目2的临床前研究进入临床环境。