Statins for Prevention of GVHD

描述(由申请人提供)：我们假设供者和受者“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)风险的有效和创新的方法。在对567例接受人类白细胞抗原相合的HCT患者的结果进行大规模回顾分析后，我们发现，捐赠者接受他汀类药物(一类具有降胆固醇和免疫调节作用的药物)之前的治疗与对严重急性GVHD的深刻保护有关。这种保护作用仅限于接受基于环孢素(CSP)的移植后免疫抑制的受者，而在给予他克莫司(TAC)的受者中观察不到。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，通过使用来自经他汀类药物治疗的人类干细胞捐赠者的T细胞，将进行旨在确定GVHD保护机制的体外研究(目标3)。在目标1中，在进行临床试验之前，我们将优化他汀类药物，该药物已被证明在犬HCT模型中具有GVHD保护作用。我们将重点关注两个指导临床试验设计的重要问题：(I)供体他汀类药物治疗的持续时间能否缩短到3周以下而不影响疗效；(Ii)仅在HCT前使用他汀类药物治疗供体(而不是受者)是否足以使GVHD保护作用生效？在目标2中，我们将启动一项前瞻性的II期临床试验，旨在评估供体(和潜在的受体)他汀类药物调节预防急性移植物抗宿主病的有效性和安全性。此外，在“国际血液和骨髓移植研究中心”(CIBMTR)批准的一项针对4500-6000名患者的观察性队列研究中，将对无关捐赠者他汀类药物的使用进行前瞻性评估，并将其与移植结果相关联。在目标3中，我们将使用体外试验来确定他汀类药物在体内暴露后T细胞功能是如何改变的。通过使用参与临床试验的他汀类药物治疗的干细胞捐献者的血液样本(目标2)，我们将检验他汀类药物损害持续T细胞激活的假设，并通过损害线粒体功能与CSP(但不是TAC)在预防GVHD方面具有协同作用。我们还将探索这一假说的替代方案。从这些研究得出的集体发现将提供评估更多患者和资源密集型III期临床试验的优点所需的初步信息。

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.