Cytokine Modulation Strategy in Clinical Allogeneic BMT

异基因骨髓移植（BMT）是许多恶性和非恶性疾病的治疗选择。当家庭捐赠者不可用时，成功的BMT可以使用志愿者，无关捐赠者（URD）完成。URD BMT后的早期死亡率仍然高得令人无法接受，并限制了该手术的成功应用。急性移植物抗宿主病（GVHD）和特发性肺炎综合征（IPS）是URD BMT后两种最重要的并发症，约占100天非复发死亡率的80%。大量的实验数据表明，包括肿瘤坏死因子（TNF α）在内的炎性细胞因子是GVHD和IPS的重要贡献者。我们最近成功地完成了两项试点试验，使用一种这样的药物，依那西普，一种可溶性，二聚体TNalpha结合蛋白治疗急性GVHD或IPS患者。这项转化研究提案将检验我们的中心假设：TNF α的中和将显著降低URD BMT后急性GVHD的发生率和100天的死亡率。项目3的具体目标是： 目的1：开展依那西普联合标准G VHD的II期临床试验 全强度URD BMT接受者的预防。 目的2：开发URD BMT后结局的生物学和遗传学预测标志物。 目的3：确定TNF α在GVHD皮肤中树突状细胞活化和角质形成细胞凋亡中的作用。 目的4：进行1/11期试验，以确定HDAC抑制剂ITF 2357的安全性， 在全强度URD BMT后给予标准GVHD预防。

AIIogeneic bone marrow transplantation (BMT) is the treatment of choice for a number of malignant and non-malignant disorders. When family donors are not available, successful BMT may be accomplished using volunteer, unrelated donors (URD). Early mortality following URD BMT remains unacceptably high and limits the successful application of this procedure. Acute g raft-versus-host disease (GVHD) and idiopathic pneumonia syndrome (IPS) are the two most significant complications following URD BMT and contribute to approximately 80% of non-relapse mortality by day 100. A significant body of experimental data has demonstrated that inflammatory cytokines including tumor necrosis factor (TNFalpha are significant contributors to GVHD and IPS. We have recently successfully completed two pilot trials using one such agent, etanercept, a soluble, dimeric TNalpha binding protein to treat patients with either acute GVHD or IPS. This translational research proposal will test our central hypothesis: That neutralization of TNFalpha will significantly reduce the rate of acute GVHD and day 100-mortality after URD BMT. The specific aims of Project 3 are: Aim1: To conduct a phase II clinical trial using etanercept in combination with standard G VHD prophylaxis in recipients of full intensity URD BMT. Aim2: To develop biologic and genetic predictive markers of outcomes after URD BMT. Aim3: To determine the role of TNFalpha in dendritic cell activation and keratinocyte apoptosis that occurs in GVHD skin. Aim4: To conduct a phase 1/11trial to determine the safety of the HDAC inhibitor, ITF2357, when given with standard GVHD prophylaxis after full intensity URD BMT.