Preclinical and Clinical Models of Drug Induced Kidney Injury

药物性肾损伤的临床前和临床模型

• 批准号: 10745197
• 负责人: Lauren M Aleksunes
• 金额: $ 63.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745197
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Animal Model; Antitumor Response; Biological; Biological Markers; Biological Products; Biology; Biopsy; CD34 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cancer Center; Cancer Model; Cancer Patient; Cancer Survivor; Cells; Chronic Kidney Failure; Clinical; Clinical Oncology; Combined Modality Therapy; Creatinine; Data; Detection; Development; Diagnostic; Drug Exposure; Drug Kinetics; Drug Modelings; Evaluation; Exhibits; Glomerular Filtration Rate; Glomerulonephritis; Goals; Guidelines; Hematopoietic; Histopathology; Human; Immune; Immune Sera; Immune checkpoint inhibitor; Immune system; Immunologic Surveillance; Immunological Models; Immunology; Immunomodulators; Immunophenotyping; Immunotherapy; Implant; Inbred BALB C Mice; Infiltration; Inflammation; Infusion procedures; Injury; Injury to Kidney; Interstitial Nephritis; Intervention; Kidney; Kinetics; Ligands; Lymphocyte; Malignant Neoplasms; Masks; Measures; Mediating; Modeling; Monitor; Mus; NCI-Designated Cancer Center; Nephrology; Newborn Infant; Nivolumab; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Pre-Clinical Model; Preclinical Testing; Proteomics; Regimen; Renal function; Research; Risk; Serum; Signal Transduction; System; T-Lymphocyte; Therapeutic; Time; Toxic effect; Toxicology; Vasculitis; acute toxicity; anti-CTLA4 antibodies; anti-PD1 antibodies; anti-cancer; cancer therapy; checkpoint therapy; circulating biomarkers; clinical practice; drug development; drug disposition; feasibility testing; follow-up; humanized mouse; immune modulating agents; immune-related adverse events; immunotoxicity; improved; innovation; ipilimumab; kidney biopsy; kidney dysfunction; mouse model; multidisciplinary; nephrotoxicity; novel; novel marker; pharmacodynamic model; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; pre-clinical assessment; preservation; prevent; programmed cell death protein 1; receptor; reconstitution; renal damage; response; restoration; translational impact; treatment response; tumor; urinary

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) are biologic drugs that have revolutionized cancer treatment by targeting specific inhibitory receptors, or their ligands, on T lymphocytes and thereby restoring immune system surveillance. Despite significant improvements in therapeutic responses, ICIs cause ‘immune-related adverse events’ (irAEs). ICI-induced immune-mediated damage to the kidneys exhibits two phenotypes including glomerulonephritis and acute kidney injury with interstitial nephritis. These kidney toxicities were not anticipated in preclinical testing but now occur in patients receiving ICIs, at a mean of 3 months of therapy. Within 5 years of receiving ICI therapy, new onset chronic kidney disease and declines in glomerular filtration rate have been observed in 20% of cancer patients. Several issues mask our understanding of ICI nephrotoxicity: 1) the ability to predict which patients will exhibit the toxicity, 2) how to sensitively detect subclinical injury prior to significant elevations in serum creatinine, and 3) poorly elucidated relationships between drug disposition, the immune system, kidney biology, and antitumor responses to inform nephrotoxicity mechanisms. There is an urgent need to develop preclinical models and assessments that can inform irAEs as ICIs are becoming the primary therapeutics for some cancers. This proposal will advance a novel mouse cancer model with a humanized immune system to identify mechanisms of kidney immunotoxicities associated with ICIs. Pharmacological interventions will evaluate the contributions of 1) tumor type, 2) drug exposure kinetics, 3) on-target versus off- target responses, and 4) human CD8+ and CD4+ lymphocyte signaling, in the mouse model of ICI nephrotoxicity. The animal model will bridge preclinical testing and clinical practice, in that the proposal will also evaluate cancer patients prescribed ICI biologics for kidney toxicities. For patients, mechanistic evaluations will be performed using quantitative systems pharmacology (QSP) and pharmacokinetic approaches. The central hypothesis of this proposal is that a novel humanized animal model recapitulates the renal pathology observed clinically with ICIs, and in combination with human biospecimens from cancer patients prescribed ICIs and novel QSP modeling can inform relationships between drug disposition, the immune system and kidney biology, antitumor responses, and nephrotoxicity to understand mechanisms of ICI renal irAEs. The proposal consists of two independent Specific Aims to systematically evaluate kidney irAEs in an animal model and clinical patients receiving ICIs. We have assembled a multidisciplinary team with expertise in clinical oncology, nephrology, immunology, pharmacokinetic and pharmacodynamic modeling, proteomics, and toxicology across two NCI-designated cancer centers to complete the proposed studies. The proposed research has high translational impact due to the current unmet need to predict, detect, and monitor kidney injury caused by ICIs and other immunomodulatory drugs with the goal of preventing long-term chronic kidney disease.

项目概要/摘要 免疫检查点抑制剂 (ICIs) 是一种生物药物，通过靶向作用彻底改变了癌症治疗 T 淋巴细胞上的特异性抑制受体或其配体并恢复免疫系统 尽管治疗反应显着改善，ICIs 仍会导致“免疫相关不良反应”。 ICI 诱导的免疫介导的肾脏损伤表现出两种表型，包括 肾小球肾炎和急性肾损伤伴间质性肾炎这些肾脏毒性是未预料到的。 在临床前测试中，但现在在接受 ICI 的患者中发生，平均治疗 3 个月后 5 年内发生。 接受 ICI 治疗、新发慢性肾脏病和肾小球滤过率下降 在 20% 的癌症患者中观察到，有几个问题掩盖了我们对 ICI 肾毒性的理解：1) 能力。 预测哪些患者会表现出毒性，2）如何在显着的损伤之前灵敏地检测亚临床损伤 血清肌酐升高，以及 3) 药物处置与免疫之间的关系尚不清楚。 迫切需要了解肾毒性机制的系统、肾脏生物学和抗肿瘤反应。 开发临床前模型和评估，为 irAE 提供信息，因为 ICI 正在成为主要的 该提案将推进一种具有人源化的新型小鼠癌症模型。 免疫系统来识别与 ICI 相关的肾脏免疫毒性机制。 干预措施将评估 1) 肿瘤类型、2) 药物暴露动力学、3) 靶向与脱靶的贡献 目标反应，4) ICI 肾毒性小鼠模型中的人 CD8+ 和 CD4+ 淋巴细胞信号传导。 该动物模型将连接临床前测试和临床实践，因为该提案还将评估癌症 对于因肾脏毒性而服用 ICI 生物制剂的患者，将进行机制评估。 使用定量系统药理学（QSP）和药代动力学方法的中心假设。 该提议是一种新颖的人源化动物模型概括了观察到的肾脏病理学 临床上使用 ICI，并与来自癌症患者的人体生物样本结合使用 ICI 新颖的 QSP 模型可以揭示药物处置、免疫系统和免疫系统之间的关系 肾脏生物学、抗肿瘤反应和肾毒性，以了解 ICI 肾脏 irAE 的机制。 该提案由两个独立的具体目标组成，旨在系统地评估动物的肾脏 irAE 我们组建了一支具有临床专业知识的多学科团队。 肿瘤学、肾病学、免疫学、药代动力学和药效学模型、蛋白质组学和 两个 NCI 指定的癌症中心进行毒理学研究，以完成拟议的研究。 由于目前预测、检测和监测肾损伤的需求尚未得到满足，因此具有很高的转化影响 通过 ICI 和其他免疫调节药物进行治疗，目的是预防长期慢性肾脏病。