Phase II Study of a Novel GVHD Prevention Strategy: Etanercept and Photopheresis

描述（由申请人提供）： 年龄大于50岁的患者构成了仅用化疗不能治愈的血液恶性肿瘤患者的大多数。由于毒性较低的降低强度预处理方案（RIT）的出现，这些老年患者代表了接受无关供体造血细胞移植（URD）的患者中增长最快的群体。这类患者对移植物抗宿主病（GVHD）和高剂量类固醇标准治疗的耐受性通常较差。因此，需要新的治疗GVHD，最严重的并发症异基因骨髓移植（BMT）。目前用于GVHD预防和治疗的药理学试剂主要靶向GVHD的基本效应物之一，供体T细胞。GVHD的其他关键因素，因此潜在的治疗靶点，是炎性细胞因子和调节性T细胞（T细胞）。我们团队开发的大量实验数据支持进行转化临床试验，以测试作用于这些额外GVHD机制的药物。首先，我们已经证明了炎症细胞因子TNF 1与GVHD密切相关。我们还在临床试验中表明，用依那西普抑制TNF是安全的，并且可能对GVHD具有临床疗效。第二，强有力的实验数据表明，TdR对GVHD发挥抑制作用。我们已经证明，体外循环血液分离术（ECP）诱导TcR在GVHD的实验模型和我们的团队，以及其他人，有数据表明，ECP可能在GVHD预防和治疗的临床疗效。在这个项目中，我们将进行一项独特的临床试验，将这两种疗法结合起来预防GVHD。GVHD的进一步发展，即治疗的个体化，目前受到阻碍，因为GVHD不能精确预测，诊断通常难以建立，并且GVHD可能对治疗有抗性的患者不能被识别。我们的团队最近确定了具有预测和诊断能力的首批GVHD生物标志物组之一。该项目产生的临床和实验室数据对于设计和执行大型临床试验至关重要，该试验将（1）明确测试这种预防GVHD的新方法，（2）纳入GVHD生物标志物。具体目标是：1。在非亲缘供者（URD）低强度移植（RIT）中，通过体外单采（ECP），使用TNF抑制剂、依那西普和调节性T细胞（Treg）诱导增强的标准GVHD预防，进行II期GVHD预防试验。2.将GVHD的细胞和血浆生物标志物与上述试验的临床结局相关联。(End摘要）

DESCRIPTION (provided by applicant): Patients older than fifty years comprise the majority of patients with hematologic malignancies that can not be cured with chemotherapy alone. Due to the advent of less toxic reduced intensity conditioning regimens (RIT), these older patients represent the fastest growing group of patients receiving unrelated donor hematopoietic cell transplant (URD). This population of patients generally poorly tolerates graft-versus-host disease (GVHD) and standard treatment with high-dose steroids. Thus new treatments are needed for GVHD, the most serious complication of allogeneic bone marrow transplantation (BMT). Current pharmacological agents for GVHD prevention and treatment primarily target one of the essential effectors for GVHD, donor T cells. Other key elements for GVHD, and therefore potential therapeutic targets, are inflammatory cytokines and regulatory T cells (Tregs). Extensive experimental data developed by our team support the conduct of translational clinical trials to test agents that act upon these additional GVHD mechanisms. First, we have demonstrated that the inflammatory cytokine, TNF1 is strongly correlated with GVHD. We have also shown in clinical trials that TNF- inhibition with etanercept is safe and may have clinical efficacy for GVHD. Second, strong experimental data demonstrates that Tregs exert an inhibitory effect on GVHD. We have shown that extracorporeal photopheresis (ECP) induces Tregs in experimental models of GVHD and our team, as well as others, has data suggesting that ECP may have clinical efficacy in GVHD prevention and treatment. In this project we will perform a unique clinical trial that combines these two therapies 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 therapy can not be identified. One of the first GVHD biomarker panels with predictive and diagnostic power was recently identified by our team. The clinical and laboratory data generated by this project is essential to design and execute a large clinical trial that will (1) definitively test this novel approach to GVHD prevention and (2) incorporate GVHD biomarkers. The Specific Aims are: 1. To conduct a phase II GVHD prevention trial using standard GVHD prophylaxis augmented by the TNF- inhibitor, etanercept, and regulatory T-cell (Treg) induction, by extracorporeal photopheresis (ECP) in unrelated donor (URD) reduced intensity transplantation (RIT). 2. To correlate cellular and plasma biomarkers of GVHD with clinical outcomes on the above trial. (End of Abstract)