Preclinical and Clinical Models of Drug Induced Kidney Injury

项目总结/摘要 免疫检查点抑制剂（ICI）是一种生物药物，通过靶向治疗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，从而恢复免疫系统 监视尽管治疗反应有显著改善，但ICI引起免疫相关不良反应。 事件（irAE）。ICI诱导的免疫介导的肾脏损伤表现出两种表型， 肾小球肾炎和急性肾损伤伴间质性肾炎。这些肾脏毒性不是预期的 在临床前试验中，但现在发生在接受ICI的患者中，平均治疗3个月。5年内 接受ICI治疗的患者中，新发慢性肾脏疾病和肾小球滤过率下降已被 在20%的癌症患者中观察到。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）如何在显著性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、免疫调节和 系统，肾脏生物学和抗肿瘤反应，以告知肾毒性机制。迫切需要 开发可告知irAE的临床前模型和评估，因为ICI正在成为主要的 一些癌症的治疗方法。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，以确定与ICI相关的肾脏免疫毒性机制。药理 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， 靶向反应，和4）人CD 8+和CD 4+淋巴细胞信号传导，在ICI肾毒性小鼠模型中。 该动物模型将连接临床前试验和临床实践，因为该提案还将评估癌症 患者处方ICI生物制剂治疗肾毒性。对于患者，将进行机械评价 使用定量系统药理学（QSP）和药代动力学方法。的中心假设 该建议是一种新的人源化动物模型重现了所观察到的肾脏病理学 在临床上使用ICI，并与来自处方ICI的癌症患者的人体生物标本联合使用 新的QSP模型可以告知药物处置，免疫系统和 肾脏生物学、抗肿瘤反应和肾毒性，以了解ICI肾脏irAE的机制。 该提案包括两个独立的特定目的，以系统评价动物肾脏irAE 模型和接受ICI的临床患者。我们组建了一个多学科团队，具有临床专业知识， 肿瘤学、肾脏学、免疫学、药代动力学和药效学建模、蛋白质组学，以及 毒理学在两个NCI指定的癌症中心完成拟议的研究。拟议研究 由于目前尚未满足预测、检测和监测肾损伤的需求， 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.