Statins for Prevention of GVHD

他汀类药物预防 GVHD

• 批准号: 8458554
• 负责人: MARCO B MIELCAREK
• 金额: $ 41.89万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-18 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458554
• 关键词: Accounting; Acute Graft Versus Host Disease; Address; Affect; Allogenic; Bioenergetics; Biological Assay; Blood; Blood specimen; CSF3 gene; Canis familiaris; Cell physiology; Cholesterol; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical Trials Design; Cohort Studies; Collection; Comparative Study; Cyclosporine; Data; Development; Evaluation; Exposure to; Graft Rejection; Graft-Versus-Tumor Induction; Hematopoietic Neoplasms; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Malignant Neoplasms; Marrow; Measures; Mediating; Metabolic; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Observational Study; Organ Transplantation; Outcome; Patients; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Prevention; Procedures; Prophylactic treatment; Recurrence; Regimen; Research; Resources; Risk; Safety; Sampling; Siblings; Solid; Stem cells; T-Cell Activation; T-Lymphocyte; Tacrolimus; Testing; Time; Translating; Transplantation; atorvastatin; base; clinical practice; conditioning; graft vs host disease; hematopoietic cell transplantation; human stem cells; improved; in vitro Assay; in vivo; innovation; international center; mortality; phase 2 study; preclinical study; prevent; prospective; protective effect; public health relevance; synergism

DESCRIPTION (provided by applicant): We hypothesize that donor and recipient "statin" treatment is an effective and innovative approach to lower the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). In a large retrospective analysis of outcomes among 567 recipients of HLA-identical HCT, we found that prior treatment of donors with statins, a class of drugs with cholesterol-lowering and immune-modulating effects, was associated with profound protection against severe acute GVHD. The protective effect was restricted to recipients given cyclosporine (CSP)-based postgrafting immunosuppression and not observed among those given tacrolimus (TAC). These findings, if confirmed, will have a significant impact on improving the safety of clinical HCT. Based on these findings, we propose to optimize a statin regimen that has been shown to be GVHD-protective in the canine HCT model (Aim 1) and translate this regimen into a clinical phase II study (Aim 2). Finally, by using T cells from statin-treated human stem cell donors, in vitro studies will be performed aimed at defining the GVHD-protective mechanisms (Aim 3). In Aim 1, before proceeding to a clinical trial, we will optimize the statin regimen that has been shown to confer GVHD-protection in the canine HCT model. We will focus on two important questions that will instruct the design of the clinical trial: (i) Can the duration of donor statin-treatment be shortened to less than 3 weeks without compromising efficacy; and (ii) is it sufficient to treat only the donor with a statin before HCT (and not the recipient) for the GVHD-protective effect to be operative? In Aim 2, we will initiate a prospective phase II clinical trial aimed at assessing efficacy and safety of donor (and potentially recipient) statin conditioning for the prevention of acute GVHD. In addition, in an observational cohort study of 4,500-6,000 patients approved by the "Center for International Blood and Marrow Transplant Research" (CIBMTR), unrelated donor statin use will be assessed prospectively and correlated with transplantation outcomes. In Aim 3, we will use in vitro assays to determine how T cell function is altered by exposure to statins in vivo. By using blood samples from statin-treated stem cell donors participating in the clinical trial (Aim 2), we will test the hypothesis that statins impair sustained T cell activation and synergize with CSP (but not TAC) in preventing GVHD by compromising mitochondrial function. Alternatives to this hypothesis will also be explored. The collective findings derived from these studies will provide preliminary information that will be needed in order to evaluate the merits of a more patient- and resource-intensive phase III clinical trial.

描述（由申请人提供）：我们假设供体和受体“他汀类药物”治疗是降低异基因造血细胞移植（HCT）后移植物抗宿主病（GVHD）风险的有效和创新方法。在一项对567例HLA相合HCT受者结局的大型回顾性分析中，我们发现，既往使用他汀类药物（一类具有降胆固醇和免疫调节作用的药物）治疗供体与严重急性GVHD的保护作用相关。保护作用仅限于给予环孢素（CSP）为基础的移植后免疫抑制的受体，而在给予他克莫司（TAC）的受体中未观察到。这些发现如果得到证实，将对提高临床HCT的安全性产生重大影响。基于这些发现，我们建议优化他汀类药物方案，该方案已被证明在犬HCT模型中具有GVHD保护作用（目标1），并将该方案转化为临床II期研究（目标2）。最后，通过使用来自他汀类药物处理的人干细胞供体的T细胞，将进行旨在定义GVHD保护机制的体外研究（目的3）。在目标1中，在进行临床试验之前，我们将优化已显示在犬HCT模型中赋予GVHD保护的他汀类药物方案。我们将重点关注指导临床试验设计的两个重要问题：（i）供体他汀类药物治疗的持续时间是否可以缩短至3周以下而不影响疗效;（ii）在HCT前仅用他汀类药物治疗供体（而不是受体）是否足以使GVHD保护作用有效？在目标2中，我们将启动一项前瞻性II期临床试验，旨在评估供体（和潜在受体）他汀类药物预处理预防急性GVHD的有效性和安全性。此外，在一项由“国际血液和骨髓移植研究中心”（CIBMTR）批准的4500 - 6000例患者的观察性队列研究中，将前瞻性评估无关供体他汀类药物的使用情况，并将其与移植结局相关联。在目标3中，我们将使用体外试验来确定体内暴露于他汀类药物如何改变T细胞功能。通过使用来自参与临床试验（目的2）的他汀类药物治疗的干细胞供体的血液样本，我们将测试他汀类药物损害持续的T细胞活化并与CSP（但不是TAC）协同作用以通过损害线粒体功能来预防GVHD的假设。还将探讨这一假设的替代办法。从这些研究中得出的集体结果将提供初步信息，以评估更多患者和资源密集型III期临床试验的优点。