WT1 Expression in Patients with MDS Treated with ATG an*

描述（由申请人提供）：仅在美国，估计每年诊断出15，000例骨髓增生异常综合征（MDS）新病例。诊断时的平均年龄约为70岁。40%至50%的患者死于感染或外周血细胞减少引起的出血;其他人发展为急性白血病。虽然造血干细胞移植提供了潜在的治愈性治疗，但目前只有一小部分患者符合条件。需要额外的治疗策略。最近的研究集中在MDS的病理生理学，试图确定治疗靶点，几个线索是有希望的。为了进一步提高治疗成功率，需要进行研究，一方面显示患者和疾病特征之间的相关性，另一方面显示对给定治疗策略的反应。我们在一项初步研究中发现，用抗胸腺细胞球蛋白（ATG）抑制自身反应性T细胞，加上依那西普（一种可溶性TNF α受体）保护正常造血，为一个亚群的患者提供了有效的治疗。本II期方案旨在证实这些发现，并将应答与自体T细胞的功能和对TNF α的特异性应答相关联。本研究将招募低风险或中风险MDS患者（根据国际预后评分系统（IPSS））。具体目标1是确定ATG和依那西普治疗的持续应答率，并确定与应答相关的患者特征。具体目标2是确定MDS患者的疾病参数和骨髓细胞的体外特征，这些参数和特征与疾病病程和治疗反应相关，目的是将这些信息应用于未来更具体的治疗干预措施的设计。具体而言，我们将通过多参数流式分析表征治疗前后的骨髓细胞，我们将确定WT 1表达，我们将评估治疗前后的T细胞库和CDS抗WT 1反应性，我们将确定HLA-DR 15（01）等位基因、MHC II类限制性T细胞（CD 4）反应和TNF α效应之间是否存在相关性。这些研究有望提高我们对MDS病理生理学特征的理解，这些特征适用于ATG免疫抑制治疗和TNF介导的信号调节。这些研究也可能进一步深入了解WT 1在MDS患者骨髓衰竭中的作用，从而为抗原导向治疗奠定基础。总体而言，该试验预计将更清楚地定义ATG和依那西普联合治疗在低级别MDS中的作用，并确定可用于开发新治疗策略的疾病特征。

DESCRIPTION (provided by applicant): An estimated 15,000 new cases of myelodysplastic syndrome (MDS) are being diagnosed annually in the United States alone. The average age at diagnosis is about 70 years. Forty percent to 50% of patients die with infections or hemorrhage due to peripheral blood cytopenias; others develop acute leukemia. While hemopoietic stem cell transplantation offers potentially curative therapy, only a small proportion of patients are currently eligible. Additional therapeutic strategies are needed. Recent investigations have focused on the pathophysiology of MDS in an attempt to identify therapeutic targets, and several leads are promising. To further improve treatment success, studies are needed that show correlations between patient and disease characteristics on one hand and response to a given therapeutic strategy on the other. We showed in a pilot study that treatment with antithymocyte globulin (ATG) to inactivate autoreactive T cells, plus etanercept (a soluble TNFa receptor) to protect normal hematopoiesis, provides effective therapy for a subpopulation of patients. The present Phase II protocol is aimed at substantiating those findings and at correlating responses with the function of autologous T cells and specific responses to TNFa. The study will enroll patients with low or intermediate-1 risk MDS (by the International Prognostic Scoring System (IPSS). Specific Aim 1 is to determine the rate of sustained responses to treatment with ATG and etanercept and to identify patient characteristics that correlate with responses. Specific Aim 2 is to identify disease parameters and in vitro characteristics of marrow cells from patients with MDS, which correlate with disease course and response to therapy, with the objective of applying that information to the design of future more specific therapeutic interventions. Specifically, we will characterize marrow cells before and after therapy by multiparameter flow analysis, we will determine WT1 expression, we will assess the T-cell repertoire and CDS anti-WT1 reactivity before and after therapy, and we will determine whether there is a correlation between the presence of the HLA-DR15(01) allele, MHC class II restricted T-cell (CD4) responses, and TNFa effects. These studies are expected to improve our understanding of the pathophysiological features of MDS that are amenable to therapy with immunosuppression with ATG and modulation of TNF-mediated signals. The studies are also likely to provide further insights into the role of WT1 in marrow failure in patients with MDS and thereby establish a basis for antigen-directed therapy. Overall, the trial is expected to more clearly define the role of combination therapy with ATG and etanercept in low grade MDS, and to identify disease characteristics that can be exploited for the development of new treatment strategies.