GVHD Clinical Trials and Biomarkers

项目总结(见说明)： 移植物抗宿主病(GVHD)是异基因移植最严重的并发症，需要新的治疗方法。 骨髓移植。预防和治疗移植物抗宿主病的药物研究进展 主要针对GVHD的基本效应之一，捐赠者T细胞。GVHD的其他关键效应器，以及 因此，潜在的治疗靶点是抗原提呈细胞(APC)。广泛的实验数据 由PPG开发，支持进行转化性临床试验，以测试在此基础上起作用的试剂 额外的GVHD机制。我们已经证明了APC功能可以被组蛋白调节 脱乙酰酶抑制剂(HDACi)，在我们发表的初步数据中，HDACi，Suberoylanalide 异羟肟酸(SAHA)，也被称为涡旋剂，调节实验性GVHD。在这个项目中将 进行这种药物预防移植物抗宿主病的独特临床试验。GVHD的进一步进展， 个体化治疗目前受到阻碍，因为GVHD不能被准确地预测， 诊断通常很难确定，GVHD患者很可能对标准治疗产生抵触 无法辨认。第一批具有预测和诊断能力的GVHD生物标志物小组之一是 在本项目支持的工作中确定L我们最近确定了多个额外的生物标志物 使用大规模蛋白质组学发现方法。在这个项目中，我们将整合新发现的 生物标记物与那些已经被验证为为同种异体基因创建信息和临床有用的面板的生物标记物 骨髓移植患者。具体目标是： 1.在标准免疫抑制药物的基础上，使用HDACi，Vorinostat进行第二阶段试验 亲缘减强度移植中移植物抗宿主病的预防 2.开发针对GVHD靶器官(皮肤和胆管)的生物标志物。 3.验证8个新发现的候选蛋白作为诊断、预后和治疗的生物标志物 系统性急性移植物抗宿主病的预测。 4.使用经过验证的组合来优化预测、诊断和预后生物标志物小组 靶器官特异性和系统性生物标记物，并分析其在新的临床试验中的价值。

PROJECT SUMMARY (See instructions): New treatments are needed for graft-vs-host disease (GVHD), the most serious complication of allogeneic bone marrow transplantation (BMT). Current pharmacologic agents for GVHD prevention and treatment primarily target one of the essential effectors for GVHD, donor T cells. Other key effectors for GVHD, and therefore potential therapeutic targets, are antigen presenting cells (APCs). Extensive experimental data developed by this PPG support the conduct of translational clinical trials to test agents that act upon this additional GVHD mechanism. We have demonstrated that APC function can be modulated by histone deacetylase inhibitors (HDACi) and in preliminary data we published, that the HDACi, suberoylanalide hydroxamic acid (SAHA), also known as vorinostat, regulates experimental GVHD. In this project will perform a unique clinical trial of this drug for GVHD prevention. A further advance in GVHD, the individualization of treatment, is presently hampered because GVHD can not be predicted precisely, the diagnosis is often hard to establish, and patients whose GVHD is likely to be resistant to standard therapy can not be identified. One of the first GVHD biomarker panels with predictive and diagnostic power was identified in work supported by this projecL We have recently identified multiple additional biomarkers using a large-scale proteomics discovery approach. In this project we will integrate newly discovered biomarkers with those already validated to create informative and clinically useful panels for allogeneic BMT patients. The Specific Aims are: 1. To conduct a Phase II trial using the HDACi, vorinostat in addition to standard immunosuppression to prevent GVHD in related donor reduced intensity transplantation 2. To develop biomarkers specific to GVHD target organs (skin and Gl tract). 3. To validate eight newly discovered candidate proteins as biomarkers for the diagnosis, prognosis and prediction of systemic acute GVHD. 4. To optimize predictive, diagnostic, and prognostic biomarker panels using validated combinations of target organ specific and systemic biomarkers and to analyze their value in new clinical trials.