Safety and efficacy of Belatacept in heart transplantation

贝拉西普在心脏移植中的安全性和有效性

• 批准号: 10622240
• 负责人: Marlena Habal
• 金额: $ 177.54万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622240
• 关键词: Acute; Adherence; Adrenal Cortex Hormones; Adverse effects; Antibodies; Autoantibodies; Autoantigens; B-Lymphocyte Subsets; Biological Assay; Biological Markers; Biopsy; CD28 gene; CD80 gene; CD86 gene; Calcineurin inhibitor; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Trials; Communities; Cytometry; Data; Development; Diabetes Mellitus; Event; FDA approved; Foundations; Freedom; Goals; Graft Survival; Health; Heart Transplantation; Helper-Inducer T-Lymphocyte; Human Herpesvirus 4; Image; Immune; Immune response; Immunology; Immunosuppression; Individual; Injury to Kidney; Kidney; Kidney Transplantation; Kinetics; Licensing; Link; Mediating; Metabolic; Molecular; Morbidity - disease rate; Multi-Institutional Clinical Trial; Multicenter Trials; Outcome; PPP3CA gene; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Populations at Risk; Prednisone; Protocols documentation; Randomized; Randomized, Controlled Trials; Regimen; Regulatory T-Lymphocyte; Renal function; Risk; Safety; Signal Transduction; Site; Survivors; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Tacrolimus; Testing; Time; Translating; Transplant Recipients; Transplantation; Tremor; Vascular Diseases; Withdrawal; arm; cell free DNA; compliance behavior; cost; design; donor-specific antibody; efficacy testing; experience; heart allograft; improved; kidney fibrosis; mycophenolate mofetil; neurotoxicity; novel; post-transplant; potential biomarker; predict clinical outcome; prevent; primary endpoint; response; safety outcomes; secondary endpoint; seropositive; standard of care; transcriptomics; trial design; virtual

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.

项目概述：虽然钙调磷酸酶抑制剂（CNIs），包括他克莫司， 心脏移植的结果，长期生存仍然受到心脏移植物血管病变的限制， 供者特异性抗体（DSA）和CNI相关的发病率，主要是慢性肾脏疾病。 Belatacept是一种选择性共刺激阻断剂，FDA批准其作为CNI用于肾移植。 替代.通过抑制CD 28/CD 80/CD 86相互作用，贝拉西普阻止了幼稚T细胞和T淋巴细胞的活化。 滤泡辅助性T细胞与DSA的发生有关，但对记忆性T细胞的抑制作用较弱。在 肾移植受者，这已转化为持续改善肾功能，抑制 DSA，并改善移植物/患者生存，尽管代价是更多的早期排斥反应， 通过使用延迟CNI取代策略显著降低。基于这些发现，我们提出了一个 首次心脏移植受者接受贝拉西普联合渐进式 停用他克莫司9个月，以达到无CNI的免疫抑制方案（含霉酚酸酯 莫非替和泼尼松）。我们假设CNI的逐渐退出会促进安静 在移植物反应性T细胞，从而防止排斥反应，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： 目标1.贝拉西普用于心脏移植安全性的临床试验。我们将执行一个 EB病毒血清阳性心脏移植受者接受贝拉西普治疗的多中心临床试验 心脏移植后逐渐停用他克莫司（9个月）或标准治疗他克莫司（对照）。 目的是：a）根据以下复合物定义的停止标准确定方案的安全性： 历史对照事件发生率和B）肾脏保留和DSA的检验功效。 目标2.共刺激阻断下CNI撤除对移植物反应性免疫应答的影响。 我们将使用最先进的免疫细胞化学技术，对供者反应性、自身抗原反应性T细胞和B细胞亚群进行系列分析。 表型和功能测定，并将量化DSA和自身抗体。结果将比较 将在个体受试者中随时间评价研究组和反应动力学。 目标3.与试验主要和次要终点相关的其他机制/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，探索肾脏标记物， 损伤和纤维化，并测试供体来源的无细胞DNA作为阻碍排斥反应的潜在生物标志物 CNI退出。如果成功，贝拉西普有可能改变心脏移植领域， CNI发病率和预防DSA是改善长期生存率的主要障碍。综合 机制研究将提供新的信息，无论试验结果如何。