Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation

肾移植中生物标志物引导的 CNI 替代评估

基本信息

批准号：
10488428
负责人：
Peter Scott Heeger
金额：
$ 413.87万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2029-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10488428
关键词：
3-Dimensional Acute Address Affect Allografting Biological Markers Biopsy Calcineurin inhibitor Canada Cessation of life Characteristics Clinical Clinical Trials Enrollment Ensure Event FDA approved Failure Future Glomerular Filtration Rate Goals HLA-DR Antigens Health Human Imaging Techniques Immune Immunologic Markers Immunologics Immunosuppression Infrastructure Infusion procedures Injury Kidney Transplantation Life Mediating Medical Molecular Molecular Profiling Morbidity - disease rate Multicenter Studies Multicenter Trials Mycophenolic Acid Neurocognitive Observational Study Outcome Outcome Measure Pathway interactions Patient Outcomes Assessments Patient Participation Patients Phenotype Population Prednisone Prognostic Marker Prospective Studies Protocols documentation Randomized Randomized Controlled Trials Research Design Retrospective Studies Risk Safety Self Administration Stratification T cell receptor repertoire sequencing T-Lymphocyte Tacrolimus Testing Therapeutic Time Toxic effect Transplant Recipients Transplantation United States National Institutes of Health Work antibody-mediated rejection arm base clinical care cohort design donor-specific antibody evidence base fibrogenesis follow-up graft function human leukocyte antigen testing immunosuppressed improved improved outcome insight instrument isoimmunity kidney allograft novel outcome prediction peripheral blood post-transplant predictive marker primary endpoint prospective prospective test racial diversity risk stratification secondary endpoint specific biomarkers standard of care subcutaneous success vasoconstriction

项目摘要

Current standard of care for kidney transplant (KTx) recipients has only modestly improved long-term aggregate graft and/or patient survival, identifying a crucial unmet medical need. As the at-risk KTx population is heterogeneous, the currently employed and relatively homogeneous therapeutic approach to immunosuppression in KTx in the US and Canada is suboptimal, and results in a significant proportion of over- immunosuppressed recipients, many with tacrolimus-related toxicities. In this U01 application, Co-PIs Heeger and Nickerson will build upon their past, productive collaborative efforts, their established multicenter trial consortium and infrastructure, as well as their expertise in biomarkers and mechanistic studies to address this unmet need. The overarching goal of the proposed work is to determine the utility of the HLA-DR/DQ molecular mismatch (mMM) score, as a risk stratifying biomarker in KTx. While retrospective studies showed strong correlations between the HLA-DR/DQ mMM score and the risk of developing biopsy proven acute rejection (BPAR) and/or donor specific antibodies (DSA), no prospective studies have tested the HLA mMM score as a risk stratifying biomarker for immunological KTx injury. Nor have any studies attempted to test whether and how the HLA-DR/DQ mMM score performs as a predictor of outcome following a change in transplant immunosuppression. Herein, we propose a multicenter observational study with a nested randomized controlled (RCT) trial to address these deficiencies. We will prospectively test the utility of the HLA-DR/DQ mMM score as a prognostic biomarker of primary alloimmunity [T cell mediated rejection (TCMR), DSA, and antibody mediated rejection (ABMR)] in KTx (Aim 1, observational study of 800 KTx). We will also test the hypothesis that the HLA-DR/DQ mMM score is a predictive biomarker that identifies KTx recipients who will tolerate substituting the calcineurin inhibitor with self-administered, subcutaneous abatacept (costimulatory blockade), without an unacceptable increased risk of BPAR, while reducing the morbidity of CNI off-target effects (300 KTx, Nested RCT with a non-inferiority endpoint, Aim 2). Accompanying mechanistic studies (Aim 3) will provide novel immunological and molecular insights that will also aid in interpreting graft and recipient outcomes of the trial. If successful, the work will provide crucial information capable of positively, and directly affecting clinical care. The results from the proposed work also have the potential to influence positively the design of future RCTs by providing an HLA-DR/DQ mMM score-based stratification or enrichment strategy for enrolling subjects into trials most likely to be informative for the proposed study agent-- thereby increasing likelihood of trial success in the shortest possible time.

目前肾移植 (KTx) 受者的护理标准仅在长期内略有改善汇总移植物和/或患者存活率，确定关键的未满足的医疗需求。作为高危 KTx 人群是异质的，目前采用的且相对同质的治疗方法美国和加拿大的 KTx 免疫抑制效果欠佳，导致很大比例的过度治疗免疫抑制的接受者，许多人患有他克莫司相关的毒性。在此 U01 申请中，Co-PIs Heeger 和尼克森将在他们过去富有成效的合作努力和已建立的多中心试验的基础上再接再厉联盟和基础设施，以及他们在生物标志物和机制研究方面的专业知识来解决这个问题未满足的需求。拟议工作的总体目标是确定 HLA-DR/DQ 的效用分子错配 (mMM) 评分，作为 KTx 的风险分层生物标志物。虽然回顾性研究表明 HLA-DR/DQ mMM 评分与活检证实急性发作的风险之间存在很强的相关性排斥（BPAR）和/或供者特异性抗体（DSA），没有前瞻性研究测试过 HLA mMM 评分作为免疫性 KTx 损伤的风险分层生物标志物。也没有任何研究试图测试 HLA-DR/DQ mMM 评分是否以及如何作为结果变化的预测因子移植免疫抑制。在此，我们提出了一项嵌套的多中心观察研究随机对照（RCT）试验旨在解决这些缺陷。我们将前瞻性地测试该功能的实用性 HLA-DR/DQ mMM 评分作为原发同种免疫的预后生物标志物 [T 细胞介导的排斥反应 (TCMR)， KTx 中的 DSA 和抗体介导的排斥反应 (ABMR)]（目标 1，800 KTx 的观察性研究）。我们也会检验 HLA-DR/DQ mMM 评分是识别 KTx 接受者的预测生物标志物的假设谁能耐受用自行皮下注射的阿巴西普替代钙调神经磷酸酶抑制剂（共刺激阻断），不会增加不可接受的 BPAR 风险，同时降低 CNI 的发病率脱靶效应（300 KTx，具有非劣效性终点的嵌套 RCT，目标 2）。伴随机械研究（目标 3）将提供新的免疫学和分子见解，这也将有助于解释移植物以及试验的接受者结果。如果成功，这项工作将提供能够积极地、并直接影响临床护理。拟议工作的结果也有可能影响通过提供基于 HLA-DR/DQ mMM 评分的分层，积极设计未来的 RCT，或者将受试者纳入试验的丰富策略最有可能为拟议的研究药物提供信息—— 从而增加在尽可能短的时间内试验成功的可能性。