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: 10334688
• 负责人: Meghan E. Sise
• 金额: $ 72.68万
• 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/10334688
• 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; 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; Lead; 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; adjudicate; autoimmune toxicity; base; biobank; body system; cancer care; cancer cell; cancer therapy; cancer type; cell type; checkpoint therapy; clinically significant; cohort; 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.

项目摘要 免疫检查点抑制剂（ICIS）正在革新癌症护理，从而产生持久的抗肿瘤反应 多种癌症类型；但是，通过释放T细胞反应，ICI可以导致免疫相关的毒性 本质上，任何器官系统都会影响60-80％的受体。保守估计，有3-5％ ICIS后患者出现急性间质性肾炎（AIN），最近的一项研究发现，多达40％的患者 收到ICI后两年的生存将经历快速估计的肾小球过滤率（EGFR）下降 （> 3毫升/分钟/年）。关于ICI诱导的肾损伤的机制知之甚少，正如所有先前发表的那样 该领域的工作具有描述性。在已发表的研究的基础上，显示出明显高的细胞毒性T细胞 ICI后与免疫相关的不良事件的活性，我们假设AIN和慢性肾脏疾病 （CKD）由ICIS产生的（CKD 肾脏。在AIM 1中，我们将招募25名具有活检的ICI诱导的AIN（ICI-AIN）和25例患者的患者 ICIS后临床审判的血流动力学AKI，并使用配对肾脏的单细胞RNA测序 活检组织，血液和尿液标本以发现ICI诱导的AIN机制。单细胞 肾脏组织的转录分析将为ICI的细胞和分子发病机理提供见解 AIN以及与血液和尿液签名进行比较的明确基准（AIM 1B）。然后我们会 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） ICIS后进行活检证明ICI-AIN的患者，以鉴定ICI-AIN独特的生物标志物 以及在以后的介入研究中靶向目标的途径。在AIM 2中，我们将确定 ICIS和长期肾脏损伤通过预期评估肾脏损伤的血液和尿液生物标志物 与对照的早期黑色素瘤患者相比，ICI治疗的黑色素瘤患者两年 仅接受外科切除术，并且不接受ICI（AIM 2A）。了解促进的机制 ICI后肾功能下降，在AIM 2B中，我们将使用Scrnaseq研究 > 20％EGFR患者的血液和尿液中的免疫和非免疫细胞转录程序 ICI后，ICI AIN患者的AIM 1B患者下降。总体而言，提出的研究将发现 ICI引起的肾脏损伤的机制具有强大的潜力，可导致ICI-AIN的非侵入性诊断， 并对T细胞抑制对肾脏功能的作用产生重要的生物学见解。提案将 利用马萨诸塞州严重免疫疗法并发症服务的专业知识 医院（MGH），是肿瘤学家和专科医生的首个多学科团队，正在研究免疫 相关的不良事件以及MGH癌症中心的巨大生物群体基础设施，推动 这些创新目标的可行性。 Stephen I. Katz早期研究员研究项目赠款是 首席研究员的新方向，启动了一项肿瘤性转化研究计划。