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

新型 GVHD 预防策略的 II 期研究：依那西普和光采术

基本信息

批准号：
8213524
负责人：
JOHN LEVINE
金额：
$ 23.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213524
关键词：
Allogeneic Bone Marrow Transplantation Allogenic Animals Area Biological Markers Biometry Blood Bone Marrow Transplantation Cell Transplants Charge Clinical Clinical Protocols Clinical Research Clinical Trials Comorbidity Complication Data Development Diagnosis Diagnostic Disease Disease remission Dose Elements Enrollment Etanercept Experimental Models Food Functional disorder Funding Goals Grant Growth Health Hematologic Neoplasms Hematopoietic Hematopoietic Stem Cell Transplantation Incidence Inflammatory Institutional Review Boards Laboratories Malignant - descriptor Malignant Neoplasms Marrow Modality Molecular Monitor Morbidity - disease rate National Heart, Lung, and Blood Institute Outcome Patients Pharmaceutical Preparations Phase Photopheresis Plasma Population Positioning Attribute Prevention Prevention strategy Program Research Project Grants Prophylactic treatment Proteins Public Health Refractory Regimen Regulatory T-Lymphocyte Relapse Research Research Design Safety Specificity Steroids Surrogate Endpoint T-Lymphocyte Testing Therapeutic Time Translating Transplantation Tumor Necrosis Factor-alpha Validation Work abstracting chemotherapy clinical efficacy conditioning cytokine design disorder prevention graft vs host disease high risk inhibitor/antagonist meetings mortality novel novel strategies older patient patient population phase 2 study prognostic programs public health relevance research study response standard care therapeutic target therapy resistant translational clinical trial

项目摘要

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) PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant diseases whose applicability has been impeded by the development of its most serious complication, GVHD. Strategies that mitigate GVHD will allow for better harnessing of this effective therapeutic modality to treat many patients with hematological cancers.

描述（由申请人提供）：五十岁以上的患者占大多数患有血液系统恶性肿瘤的患者，仅靠化疗无法治愈。由于毒性较小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。该人群通常对移植物抗宿主病（GVHD）和高剂量类固醇标准治疗的耐受性较差。因此，需要新的治疗方法来治疗移植物抗宿主病（GVHD），这是同种异体骨髓移植（BMT）最严重的并发症。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 的其他关键因素以及潜在的治疗靶点是炎症细胞因子和调节性 T 细胞 (Treg)。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，我们证明炎症细胞因子 TNF1 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。其次，强有力的实验数据表明Tregs对GVHD具有抑制作用。我们已经证明体外光采术 (ECP) 在 GVHD 实验模型中诱导 Tregs，我们的团队以及其他人的数据表明 ECP 可能在 GVHD 预防和治疗中具有临床功效。在这个项目中，我们将进行一项独特的临床试验，结合这两种疗法来预防 GVHD。 GVHD的进一步发展，即个体化治疗，目前受到阻碍，因为GVHD无法准确预测，诊断往往难以确定，并且无法识别GVHD可能对治疗产生耐药性的患者。我们的团队最近确定了第一个具有预测和诊断能力的 GVHD 生物标志物组合。该项目生成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，该临床试验将（1）明确测试这种新的 GVHD 预防方法，以及（2）纳入 GVHD 生物标志物。具体目标是： 1. 在无关供体 (URD) 中通过体外光采术 (ECP) 进行 II 期 GVHD 预防试验，使用标准 GVHD 预防，并辅以 TNF 抑制剂、依那西普和调节性 T 细胞 (Treg) 诱导。降低强度移植（RIT）。 2. 将 GVHD 的细胞和血浆生物标志物与上述试验的临床结果相关联。（摘要完）公共卫生相关性：同种异体造血干细胞移植是许多恶性疾病的潜在治疗方法，但其应用却因其最严重的并发症 GVHD 的发展而受到阻碍。减轻 GVHD 的策略将允许更好地利用这种有效的治疗方式来治疗许多血液癌症患者。