Preclinical and Clinical Models of Drug Induced Kidney Injury

项目摘要/摘要 免疫检查点抑制剂(ICIS)是一种生物药物，它通过靶向治疗癌症发生了革命性的变化。 T淋巴细胞上的特异性抑制受体或其配体，从而恢复免疫系统 监视系统。尽管治疗反应有显著改善，ICIS仍会引起免疫相关的不良反应 事件(IrAEs)。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合并间质性肾炎。这些肾脏毒性是意想不到的 在临床前测试中，但现在发生在接受ICIS的患者中，平均治疗3个月。5年内 接受ICI治疗后，新发的慢性肾脏疾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) 为了预测哪些患者将表现出毒性，2)如何敏感地在显著 血清肌酐升高，以及3)药物处置和免疫之间的关系解释不清。 系统、肾脏生物学和抗肿瘤反应，以告知肾毒性机制。有一个迫切的需要 开发临床前模型和评估，以告知irAEs作为ICIS正在成为主要的 一些癌症的治疗学。这一建议将推进一种新的小鼠癌症模型的人源化 免疫系统以确定与ICIS相关的肾脏免疫毒性的机制。药理作用 干预措施将评估1)肿瘤类型，2)药物暴露动力学，3)靶向与非靶点- 靶向反应，以及4)人CD8+和CD4+淋巴细胞信号，在ICI肾毒性小鼠模型中。 该动物模型将架起临床前试验和临床实践的桥梁，因为该提案还将评估癌症 患者为肾脏毒性开了ICI生物制剂。对于患者，将进行机械性评估 使用定量系统药理学(QSP)和药代动力学方法。的中心假说 这一建议是一种新的人源化动物模型，它概括了观察到的肾脏病理。 临床上使用ICIS，并结合来自癌症患者的人类生物标本开出ICIS 而新的QSP模型可以告知药物处置、免疫系统和 肾生物学、抗肿瘤反应和肾毒性以了解ICI肾irAEs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irAEs。 接受ICIS治疗的模型和临床患者。我们已经组建了一支拥有临床专业知识的多学科团队 肿瘤学、肾脏学、免疫学、药代动力学和药效学模型、蛋白质组学和 NCI指定的两个癌症中心的毒理学研究，以完成拟议的研究。拟议的研究 由于当前未满足预测、检测和监控导致的肾脏损伤的需求，因此具有很高的转换影响 通过ICIS和其他免疫调节药物，目的是预防长期慢性肾脏疾病。

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.