GVHD Clinical Trials and Biomarkers

GVHD 临床试验和生物标志物

基本信息

批准号：
8725946
负责人：
JOHN LEVINE
金额：
$ 19.59万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725946
关键词：
Acute Allogeneic Bone Marrow Transplantation Allogenic Antigen-Presenting Cells Area Biological Biological Markers Blood Bone Marrow Transplantation Cell physiology Clinical Protocols Clinical Research Clinical Trials Clinical Trials Design Comorbidity Complication Data Development Diagnosis Diagnostic Disease Disease Pathway Dose Functional disorder Goals Growth Hematopoietic Stem Cell Transplantation Histone Deacetylase Inhibitor Hydroxamic Acids Immunosuppression Instruction Laboratories Malignant - descriptor Malignant Neoplasms Marrow Modality Molecular Organ Patients Pharmaceutical Preparations Phase II Clinical Trials Plasma Population Prevention strategy Process Prognostic Marker Prophylactic treatment Proteins Proteome Proteomics Publishing Regimen Research Resistance Risk Sampling Sensitivity and Specificity Skin Steroids Symptoms T-Lymphocyte Technology Testing Therapeutic Translating Transplantation Ursidae Family Vorinostat Work base conditioning disease diagnosis disorder prevention graft vs host disease high risk mortality novel older patient outcome forecast patient population prevent prognostic standard care therapeutic target translational clinical trial

项目摘要

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.

项目摘要（参见说明）：移植物抗宿主病（GVHD）是同种异体移植最严重的并发症，需要新的治疗方法骨髓移植（BMT）。目前用于 GVHD 预防和治疗的药物主要针对 GVHD 的重要效应物之一——供体 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呈递细胞（APC）。丰富的实验数据该 PPG 开发的产品支持转化临床试验的进行，以测试作用于此的药物额外的GVHD机制。我们已经证明APC功能可以通过组蛋白调节脱乙酰酶抑制剂 (HDACi)，在我们发布的初步数据中，HDACi、辛二酰苯内酯 (suberoylanalide) 异羟肟酸 (SAHA)，也称为伏立诺他，调节实验性 GVHD。在这个项目中将对该药物进行独特的临床试验以预防 GVHD。 GVHD 的进一步进展由于 GVHD 无法准确预测，个体化治疗目前受到阻碍，诊断通常很难确定，GVHD 患者可能对标准治疗产生耐药性无法识别。首批具有预测和诊断能力的 GVHD 生物标志物组合之一是在该项目支持的工作中发现了我们最近发现了多种其他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志物与那些已经验证的生物标志物可以为同种异体创建信息丰富且临床有用的组合骨髓移植患者。具体目标是： 1. 使用 HDACi、伏立诺他以及标准免疫抑制进行 II 期试验预防相关供者低强度移植中的 GVHD 2.开发针对GVHD靶器官（皮肤和胃肠道）的特异性生物标志物。 3. 验证八种新发现的候选蛋白作为诊断、预后和诊断的生物标志物全身急性 GVHD 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组靶器官特异性和全身生物标志物，并分析其在新的临床试验中的价值。