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.

项目摘要：尽管包括他克莫司在内的钙调神经磷酸酶抑制剂 (CNI) 已取得了优异的 1 年疗效 心脏移植的结果，长期生存仍然受到心脏同种异体移植血管病变的限制，驱动 供体特异性抗体 (DSA) 和 CNI 相关发病率（主要是慢性肾病）。 Belatacept 是一种选择性共刺激阻滞剂，已被 FDA 批准作为 CNI-用于肾移植 选择。通过抑制 CD28/CD80/CD86 相互作用，贝拉西普可防止幼稚 T 细胞和 滤泡辅助 T 细胞与 DSA 的发展相关，但抑制记忆 T 细胞的效果较差。在 肾移植受者，这已转化为肾功能的持续改善，抑制 DSA，并改善了移植物/患者的存活率，尽管其代价是更多的早期排斥反应，此后 通过使用延迟 CNI 替代策略显着减少。基于这些发现，我们提出了 贝拉西普在首次心脏移植受者中的随机对照试验，结合逐步 他克莫司停药 9 个月以上，以实现无 CNI 的免疫抑制方案（联合霉酚酸酯 莫非替尔和泼尼松）。我们假设 CNI 逐步退出将促进平静 移植物反应性 T 细胞中，从而防止排斥反应，抑制 DSA 的发展，并消除 CNI- 相关的发病率，共同提高心脏移植后的生存率。具体目标是： 目标 1. 确定贝拉西普在心脏移植中安全性的临床试验。我们将执行一个 在 EBV 血清阳性心脏移植受者中进行的多中心临床试验，按 2:1 随机接受贝拉西普治疗 心脏移植后逐渐停用他克莫司（9 个月）或标准护理他克莫司（对照）。 目标是 a) 根据由组合定义的停止标准建立方案的安全性 历史控制事件率和 b) 测试肾脏保留和 DSA 的功效。 目标 2. 共刺激阻断下 CNI 撤药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体反应性和自身抗原反应性 T 细胞和 B 细胞亚群 表型和功能测定，并将量化 DSA 和自身抗体。结果将进行比较 随着时间的推移，研究组和反应动力学将在个别受试者中进行评估。 目标 3. 与试验中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定义移植物反应的差异，探索肾脏标志物 损伤和纤维化，并测试供体来源的无细胞 DNA 作为阻止排斥反应的潜在生物标志物 CNI 撤回。如果成功，贝拉西普有可能改变心脏移植领域，消除 CNI 发病率和预防 DSA 是改善长期生存的主要障碍。全面的 无论试验结果如何，机制研究都将提供新颖的信息。