Mechanisms driving acute and chronic kidney function decline after immune checkpoint inhibitor therapy for cancer

免疫检查点抑制剂治疗癌症后导致急性和慢性肾功能下降的机制

• 批准号: 10576290
• 负责人: Meghan E. Sise
• 金额: $ 72.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576290
• 关键词: Acute; Adaptive Immune System; Address; Affect; Albuminuria; Antitumor Response; Automobile Driving; Benchmarking; Biological; Biological Markers; Biopsy; Blood; Cancer Center; Cancer Patient; Caring; Cell physiology; Cells; Chronic; Chronic Kidney Failure; Clinical; Cytotoxic T-Lymphocytes; Development; Diagnosis; Disinhibition; Eligibility Determination; Enrollment; Excision; Exhibits; Future; Gene Expression Profiling; General Hospitals; Genetic Transcription; Genomics; Glomerular Filtration Rate; Goals; Healthcare Systems; Immune; Immune checkpoint inhibitor; Immunotherapy; Inflammatory; Infrastructure; Injury; Injury to Kidney; Interleukin-6; Interstitial Nephritis; Intervention Studies; Kidney; Kidney Diseases; Lymphocytic Infiltrate; Malignant Neoplasms; Massachusetts; Measures; Mediating; Molecular; Monoclonal Antibodies; Oncologist; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Principal Investigator; Publishing; Renal function; Research Design; Research Personnel; Research Project Grants; Role; Services; Specimen; Survivors; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; TNF gene; Technology; Time; Tissues; Toxic effect; Urine; Work; adjudication; autoimmune toxicity; biobank; biomarker identification; body system; cancer care; cancer cell; cancer therapy; cancer type; cell type; checkpoint therapy; clinically significant; cohort; comparison control; cytokine; epidemiology study; experience; hemodynamics; high risk population; immune-related adverse events; inhibiting antibody; innovation; insight; kidney biopsy; melanoma; member; multidisciplinary; noninvasive diagnosis; novel diagnostics; novel therapeutic intervention; prevent; programs; prospective; protein biomarkers; recruit; side effect; single-cell RNA sequencing; therapy design; translational research program

PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) are revolutionizing cancer care, producing durable anti-tumor responses in multiple cancer types; however, by unleashing T-cell responses, ICIs can lead to immune-related toxicities in essentially any organ system, affecting 60-80% of recipients. It is conservatively estimated that 3-5% of patients develop acute interstitial nephritis (AIN) after ICIs, and a recent study found that up to 40% of patients that survive 2 years after receiving ICIs will experience rapid estimated glomerular filtration rate (eGFR) decline (>3mL/min/year). Very little is known about the mechanisms of ICI-induced kidney injury, as all prior published work in the field has been descriptive. Building on published studies showing distinctly high cytotoxic T-cell activity in immune-related adverse events after ICIs, we hypothesize that AIN and chronic kidney disease (CKD) that result from ICIs exist on a spectrum of T-cell mediated injury to the tubulointerstitial compartment of the kidney. In Aim 1, we will enroll 25 patients with biopsy-proved ICI-induced AIN (ICI-AIN) and 25 patients with clinically-adjudicated hemodynamic AKI after ICIs and use single-cell RNA sequencing of paired kidney biopsy tissue, blood, and urine specimens to uncover mechanisms of ICI-induced AIN. Single-cell transcriptional profiling of kidney tissue will offer insights into the cellular and molecular pathogenesis of ICI- AIN as well as a clear benchmark against which to compare blood and urine signatures (Aim 1B). We will then compare cell-based transcriptional biomarkers (Aim 1C) and cytokine biomarkers (Aim 1D) in blood and urine of patients with biopsy-proven ICI-AIN to hemodynamic AKI after ICIs to identify biomarkers unique for ICI-AIN and pathways to target in future interventional studies. In Aim 2, we will determine the relationship between ICIs and long-term kidney injury by prospectively evaluating blood and urine biomarkers of kidney injury over two years in ICI-treated patients with melanoma compared to control patients with early-stage melanoma who undergo surgical resection alone and do not receive ICIs (Aim 2A). To understand mechanisms promoting kidney function decline after ICIs, in Aim 2B, we will use scRNAseq to investigate the similarities between immune and non-immune cell transcriptional programs in blood and urine among patients with >20% eGFR decline after ICIs to patients with ICI-AIN from Aim 1B. In aggregate, the studies proposed will uncover mechanisms of ICI-induced kidney injury, have strong potential to lead to non-invasive diagnostics for ICI-AIN, and yield important biological insights into the role of T-cell disinhibition on kidney function. The proposal will capitalize on the expertise of the Severe Immunotherapy Complications Service at Massachusetts General Hospital (MGH), a first-of-its kind multidisciplinary team of oncologists and subspecialists studying immune- related adverse events, and the tremendous biobanking infrastructure of the MGH Cancer Center, driving the feasibility of these innovative aims. This Stephen I. Katz Early Stage Investigator Research Project Grant is a new direction for the principal investigator, launching a translational research program in onconephrology.

项目概要 免疫检查点抑制剂 (ICIs) 正在彻底改变癌症治疗，在癌症中产生持久的抗肿瘤反应 多种癌症类型；然而，通过释放 T 细胞反应，ICIs 可能会导致免疫相关毒性 基本上是任何器官系统，影响 60-80% 的接受者。保守估计3-5% 患者在 ICI 后出现急性间质性肾炎 (AIN)，最近的一项研究发现高达 40% 的患者 接受 ICI 后存活 2 年的患者将经历估计肾小球滤过率 (eGFR) 快速下降 (>3mL/分钟/年)。正如之前发表的所有文章一样，关于 ICI 引起的肾损伤的机制知之甚少 该领域的工作是描述性的。基于已发表的研究显示 T 细胞具有明显高的细胞毒性 ICI 后免疫相关不良事件的活性，我们假设 AIN 和慢性肾病 由ICIs引起的CKD（CKD）存在于一系列T细胞介导的肾小管间质室损伤中 肾脏。在目标 1 中，我们将招募 25 名经活检证实患有 ICI 诱发的 AIN (ICI-AIN) 的患者和 25 名患者 ICI 后经临床判定的血流动力学 AKI，并使用配对肾脏的单细胞 RNA 测序 活检组织、血液和尿液标本以揭示 ICI 诱导的 AIN 机制。单细胞 肾组织的转录谱分析将有助于深入了解 ICI 的细胞和分子发病机制 AIN 以及比较血液和尿液特征的明确基准（目标 1B）。我们随后将 比较血液和尿液中基于细胞的转录生物标志物 (Aim 1C) 和细胞因子生物标志物 (Aim 1D) 活检证实 ICI-AIN 的患者在 ICI 后出现血流动力学 AKI，以确定 ICI-AIN 特有的生物标志物 以及未来干预研究的目标途径。在目标 2 中，我们将确定之间的关系 通过前瞻性评估肾损伤的血液和尿液生物标志物来研究 ICI 和长期肾损伤 与早期黑色素瘤对照患者相比，接受 ICI 治疗的黑色素瘤患者的治疗时间延长了两年 仅接受手术切除且不接受 ICI（目标 2A）。了解促进机制 ICI 后肾功能下降，在 Aim 2B 中，我们将使用 scRNAseq 来研究之间的相似性 eGFR > 20% 患者血液和尿液中的免疫和非免疫细胞转录程序 目标 1B 的 ICI-AIN 患者在 ICI 后下降。总的来说，拟议的研究将揭示 ICI 诱导的肾损伤机制，具有强大的潜力，可用于 ICI-AIN 的非侵入性诊断， 并对 T 细胞去抑制对肾功能的作用产生重要的生物学见解。该提案将 利用马萨诸塞州综合医院严重免疫治疗并发症服务的专业知识 医院（MGH）是首个由肿瘤学家和研究免疫的亚专家组成的多学科团队 相关不良事件以及麻省总医院癌症中心庞大的生物样本库基础设施，推动了 这些创新目标的可行性。斯蒂芬·卡茨早期研究员研究项目补助金是 主要研究者的新方向，启动肿瘤肾病学转化研究项目。