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

• 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
• 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

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。 总移植物和/或患者存活率，识别关键的未满足的医疗需求。作为KTx高危人群， 是异质的，目前采用的和相对同质的治疗方法， 在美国和加拿大，KTx的免疫抑制是次优的，并导致显著比例的过度- 免疫抑制受体，许多与他克莫司相关的毒性。在U 01申请中，Co-PI Heeger 和尼克森将建立在他们过去富有成效的合作努力，他们建立的多中心试验， 财团和基础设施，以及他们在生物标志物和机制研究方面的专业知识，以解决这一问题 未满足的需求所提出的工作的总体目标是确定HLA-DR/DQ的实用性 分子错配（mMM）评分，作为KTx的风险分层生物标志物。回顾性研究显示， HLA-DR/DQ mMM评分与发生活检证实的急性 排斥反应（BPAR）和/或供体特异性抗体（DSA），尚未有前瞻性研究测试了HLA mMM 评分作为免疫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改变后结果的预测因子， 移植免疫抑制在此，我们提出了一项多中心观察性研究， 随机对照试验（RCT）旨在解决这些缺陷。我们将前瞻性地测试 HLA-DR/DQ mMM评分作为原发性同种异体免疫的预后生物标志物[T细胞介导的排斥反应（TCMR）， DSA和抗体介导的排斥反应（ABMR）]（目的1，800 KTx的观察性研究）。我们还将 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 其将耐受用自我施用的皮下阿巴西普替代钙调磷酸酶抑制剂 （共刺激阻断），没有不可接受的BPAR风险增加，同时降低CNI的发病率 脱靶效应（300 KTx，具有非劣效性终点的巢式RCT，目标2）。伴随机制 研究（目标3）将提供新的免疫学和分子学见解，也将有助于解释移植物 和受试者的结果。如果成功，这项工作将提供重要的信息， 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 最有可能为拟定研究药物提供信息的试验入组受试者的富集策略-- 从而在尽可能短的时间内增加试验成功的可能性。