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 慢性移植物抗宿主病（cGVHD）是异基因造血最重要的长期不良后果 细胞移植（HCT）。造成 HCT 1-2 年后发生的大部分死亡的原因是 cGVHD 也是 HCT 后慢性发病和生活质量下降的重要原因。这 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，以及 项目 1 致力于专门针对 B 细胞区室进行预防和治疗的临床试验。 cGVHD 的治疗。在具体目标 1 中，我们针对临床前 cGVHD 采取预防策略，旨在 在 HCT 后早期重建时消耗 B 细胞。在上一个资助期间进行的第二阶段研究中， 我们提出了这样的假设：HCT 后早期施用单克隆抗体利妥昔单抗， 将降低 cGVHD 的发生率和严重程度，从而显着减少全身皮质类固醇的使用。尽管 有效，但预防不完全，所以我们现在计划进行一项 B 细胞的多中心、随机 II 期试验 使用新型第二代抗体消除 cGVHD 作为预防策略。认识 认为B细胞本身不能单独负责cGVHD的发生，我们结合B细胞的策略 在特定目标 2 中，使用利妥昔单抗进行消耗，并使用低剂量 IL-2 增强调节性 T 细胞 (TREG)。 在之前的资助期间，我们能够证明 IL-2 能够增加流通的数量 TREG 细胞，这与已确定的类固醇难治性 cGVHD 的临床反应相关。在这个项目中 我们探索了这种双管齐下的方法在新诊断的 cGVHD 患者中的效用，试图 更有效地治疗cGVHD并预防cGVHD的长期后遗症。具体目标 3 将检查 用于治疗晚期 cGVHD 的一系列有前途的化合物，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信号通路。在赠款化合物的晚年 具有活性的药物将在 cGVHD 的发展中更早地应用。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紧密相连。在项目 1 中，我们扩展了基本的 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。