Preclinical and Clinical Models of Drug Induced Kidney Injury

项目总结/文摘

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.