Safety and efficacy of Belatacept in heart transplantation

项目摘要：尽管钙调神经磷酸酶抑制剂(CNI)，包括他克莫司，已导致优秀的1年 心脏移植的结果，长期存活仍然受到同种异体心脏移植物血管病变的限制 通过供者特异性抗体(DSA)和CNI相关发病率，以慢性肾脏疾病为主。 贝拉塔塞普是一种选择性共刺激阻滞剂，FDA批准将其作为CNI-1用于肾移植。 另类选择。Belatacept通过抑制CD28/CD80/CD86相互作用阻止幼稚T细胞和 T滤泡辅助细胞与DSA的发展有关，但对记忆性T细胞的抑制作用较差。在……里面 肾移植受者，这已转化为肾功能的持续改善，抑制 DSA，并改善移植物/患者的存活率，尽管代价是更多的早期排斥反应，自那以来 通过使用延迟的CNI替换策略显著减少。基于这些发现，我们提出了一个 贝拉泰普联合渐进式治疗首次心脏移植受者的随机对照试验 他克莫司停用9个月以实现无CNI免疫抑制方案(含霉酚酸酯 莫非替尔和泼尼松)。我们假设，逐步退出CNI将促进平静 在移植物反应性T细胞中，从而防止排斥，抑制DSA的发展，并消除CNI- 相关的发病率，共同增加心脏移植后的存活率。具体目标是： 目的1.确定贝拉塔塞特在心脏移植中的安全性。我们将表演一场 EB病毒血清阳性心脏移植受者随机2：1接受贝拉西普治疗的多中心临床试验 心脏移植后逐步停用他克莫司(9个月)或标准护理他克莫司(对照组)。 其目标是：a)基于由以下内容组合定义的停止标准来确定协议的安全性 历史对照事件发生率和b)肾脏保留和DSA的测试效果。 目的2.共刺激阻断下CNI戒断对移植物反应性免疫反应的影响。 我们将使用最先进的技术连续分析供者反应性和自身抗原反应性T细胞和B细胞亚群 表型和功能分析，并将量化DSA和自身抗体。结果将与以下结果进行比较： 研究武器和反应的动力学将随着时间的推移在单个受试者中进行评估。 目的3.与试验中的主要和次要终点相关的其他机械学/生物标志物研究。 我们将使用分子方法来确定移植物内反应的差异，探索肾脏的标志物 损伤和纤维化，并测试供体来源的无细胞DNA作为潜在的阻止排斥反应的生物标记物 CNI取款。如果成功，贝拉塔塞特有可能改变心脏移植领域，移除 CNI-发病率和预防DSA是提高长期存活率的主要障碍。全面的 无论试验结果如何，机械论研究都将提供新的信息。

Project Summary: Although calcineurin inhibitors (CNIs), including tacrolimus have led to excellent 1-year outcomes in heart transplantation, long-term survival remains limited by cardiac allograft vasculopathy, driven by donor-specific-antibodies (DSA), and by CNI-associated morbidity, dominated by chronic kidney disease. Belatacept, a selective costimulation blocker, is FDA approved for use in kidney transplantation as a CNI- alternative. By inhibiting CD28/CD80/CD86 interactions belatacept prevents activation of both naïve T cell and T follicular helper cells associated with the development of DSA, but less effectively inhibits memory T cells. In kidney transplant recipients, this has translated to sustained improvement in kidney function, suppression of DSA, and improved graft/patient survival, albeit at the cost of more early rejection which has since been markedly reduced by using a delayed CNI substitution strategy. Building on these findings, we propose a randomized controlled trial of belatacept in first-time heart transplant recipients, in conjunction with gradual tacrolimus withdrawal over 9-months to achieve a CNI-free immunosuppressive regimen (with mycophenolate mofetil and prednisone). We hypothesize that the gradual approach to CNI withdrawal will promote quiescence in graft-reactive T cells, thereby preventing rejection, inhibiting the development of DSA, and eliminating CNI- related morbidity, together increasing survival after heart transplantation. The specific aims are: Aim 1. Clinical trial to determine safety of belatacept in heart transplantation. We will perform a multicenter clinical trial in EBV seropositive heart transplant recipients randomized 2:1 to receive belatacept with gradual tacrolimus withdrawal (9-months) post-heart transplant or standard-of-care tacrolimus (control). The objectives are to a) establish safety of the protocol based on stopping criteria defined by the composite of historical control event rates and b) test efficacy for kidney sparing and DSA. Aim 2. Impact of CNI withdrawal under costimulation blockade on graft-reactive immune responses. We will serially analyze donor reactive, and autoantigen reactive T cell and B cell subsets using state-of-the-art phenotypic and functional assays and will quantify DSA and autoantibodies. Results will be compared between study arms and the kinetics of responses will be evaluated in individual subjects over time. Aim 3. Other mechanistic/biomarker studies relevant to primary and secondary endpoints in the trial. We will use molecular approaches to define differences in the intragraft response, explore markers of kidney injury and fibrosis, and test donor derived cell-free DNA as a potential biomarker of impeding rejection during CNI withdrawal. If successful, belatacept has the potential to transform the heart transplant field, removing CNI-morbidities and preventing DSA as major barriers to improving long-term survival. The comprehensive mechanistic studies will provide novel information, regardless of outcomes of the trial.