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

项目摘要/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)。对发生在HCT后1-2年的大部分死亡负有责任， 慢性移植物抗宿主病也是HCT后慢性发病率和生活质量下降的重要原因。这个 这项建议的主要主题是研究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细胞室的临床试验，以预防和 CGVHD的治疗。在具体目标1中，我们以临床前cGVHD为目标，采取预防策略，旨在 当B细胞在HCT后早期重建时耗尽B细胞。在前一个供资期间进行的第二阶段研究中， 我们提出的假设是，HCT后早期给予单抗利妥昔单抗， 将降低cGVHD的发生率和严重程度，显著减少全身皮质类固醇的使用。而当 有效，预防是不完整的，所以我们现在计划进行一项多中心、随机的B细胞II期试验 使用一种新的第二代抗体将耗竭作为预防cGVHD的策略。认识 B细胞本身不能单独对cGVHD的发生负责，我们结合B细胞的策略 利妥昔单抗耗竭，调节性T细胞(Treg)增强，低剂量IL-2用于特定目的2。 在之前的资助期，我们能够证明IL-2能够增加循环中的数量 Treg细胞，这与激素难治性慢性移植物抗宿主病的临床反应相关。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患者中的有效性，试图 更有效地治疗cGVHD，预防cGVHD的长期后遗症。《特定目标3》将考察一个 一系列有希望治疗晚期cGVHD的化合物，所有这些化合物都以B细胞为靶点，或者 通过B细胞受体或相关的信号通路。在格兰特大院的最后几年 活动将在慢性移植物抗宿主病的早期开发中应用。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。

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.