Project 3

项目3

基本信息

批准号：
10434089
负责人：
MICHELLE KROGSGAARD
金额：
$ 28.32万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10434089
关键词：
Adjuvant Adjuvant Study American Antibodies Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes Biological Assay Biological Markers Bladder Cancer Patient Clinical Clinical Laboratory Improvement Amendments Clinical Trials Colitis Data Dermatologic Development Diarrhea Endocrine Exposure to Goals Hepatic Human Immune Immune checkpoint inhibitor Immunoglobulin G Immunologic Adjuvants Immunologic Markers Immunosuppression Inflammatory Bowel Diseases Kidney Laboratories Length Lung Malignant Neoplasms Morbidity - disease rate Nivolumab Oncologist Organ Pathogenicity Pathologist Patients Phase Phase II Clinical Trials Placebo Control Placebos Preclinical Testing Predisposition Prevention Prevention strategy Proteins Proteome Proteomics Publishing Randomized Recurrence Regimen Renal Cell Carcinoma Resected Role Selection for Treatments Serum T-Lymphocyte TNF gene Testing Therapeutic Thyroiditis Toxic effect Ulcerative Colitis Validation Work anti-CTLA4 anti-PD-1 base biomarker signature biomarker-driven cancer type checkpoint inhibition cohort college experience experimental study gastrointestinal high risk humanized mouse immune-related adverse events infliximab interest ipilimumab melanoma mouse model pembrolizumab phase 2 study phase II trial predicting response predictive test predictive tools prevent prophylactic response tool treatment optimization treatment strategy tumor

项目摘要

PROJECT 3 SUMMARY Immune checkpoint inhibitors have transformed melanoma treatment, producing durable responses, prolonged survival, and clinical benefit in a significant proportion of patients. Moreover, they delay recurrence and extend survival in the adjuvant melanoma setting, and have also shown efficacy in a range of different cancer types. However, immune checkpoint inhibition (ICI) therapy can also be accompanied by immune-related adverse events (irAEs) that impact multiple organs, cause significant morbidity, and require immunosuppression or discontinuation of ICI treatment. There is an urgent need to identify patients who will develop severe irAEs from ICI. This would enable us to optimize treatment selection and sequencing, justify preventive strategies to mitigate toxicity, and better manage toxicities. While there is intense interest in identifying markers to predict response to ICI, no pre-treatment biomarker tool can predict irAEs associated with ICI for any cancer type. The goal of our project is to develop a predictive tool that enables clinicians to minimize exposure of patients to severe toxicity, while maximizing clinical benefit from ICI. We hypothesize that a subset of melanoma patients has a baseline, sub-clinical autoimmune susceptibility, characterized by specific pre-existing autoantibodies (autoAbs) that can predict and exacerbate the development of toxicity from ICI therapy. We have identified autoAb signatures in baseline (pre-treatment) sera that predict severe immune toxicity in melanoma patients treated with ICI (AUC >0.95). Using a humanized mouse model, we found that autoAbs from baseline sera of melanoma patients can exacerbate irAEs from ICI. In this project, we propose to refine and validate baseline autoAb biomarker signatures of ICI toxicity using sera (n=600) from two large adjuvant ICI clinical trials for resected stage-III/IV melanoma (Aim 1). To understand the relevance of specific autoAbs to common irAEs (e.g., colitis) and to investigate an autoimmune predisposition in some patients, we will compare irAE-associated autoAbs with those from inflammatory bowel disease patients and from normal donors. We will use our humanized FcR mouse model to determine the cause-effect relationship between autoAbs and irAEs, with a focus on colitis, and for preclinical testing of prophylactic anti-TNF- as a strategy to mitigate gastrointestinal (GI) toxicity from ICI (Aim 2). These findings will inform a biomarker-driven phase-II trial of prophylactic anti-TNF- (infliximab) in patients receiving ICI therapy who are at high risk for developing severe diarrhea and colitis (Aim 3). Our work will inform personalized melanoma treatment strategies by validating a robust pre-treatment biomarker to enable clinicians to optimize ICI regimens and minimize patient exposure to severe irAEs. We will both identify an autoimmune susceptibility to irAE development and establish whether prophylactic TNF- blockade mitigates development of GI toxicity from ICI in patients identified as being at high risk of these irAEs.

项目 3 摘要免疫检查点抑制剂改变了黑色素瘤的治疗方法，产生持久的反应，延长治疗时间此外，它们还可以延迟复发并延长患者的生存期和临床获益。其在黑色素瘤辅助治疗中的生存率，并且在一系列不同的癌症类型中也显示出疗效。然而，免疫检查点抑制（ICI）治疗也可能伴随着免疫相关的不良反应。影响多个器官、导致严重发病并需要免疫抑制或迫切需要确定因 ICI 治疗而发生严重 irAE 的患者。 ICI。这将使我们能够优化治疗选择和排序，证明预防策略的合理性以减轻影响。毒性，并更好地管理毒性，同时人们对识别标记物来预测反应非常感兴趣。 ICI，没有任何治疗前生物标志物工具可以预测与任何癌症类型的 ICI 相关的 irAE。该项目的目的是开发一种预测工具，使指挥官能够最大程度地减少患者遭受严重感染的风险毒性，同时最大限度地提高 ICI 的临床效益。我们追求黑色素瘤患者的一个子集具有基线、亚临床自身免疫性易感性，以特定的预先存在的自身抗体（autoAbs）为特征，可以预测和加剧 ICI 治疗毒性的发展我们已在基线中鉴定出自身抗体特征。（治疗前）血清可预测接受 ICI 治疗的黑色素瘤患者的严重免疫毒性（AUC >0.95）。使用人源化小鼠模型，我们发现来自黑色素瘤患者基线血清的自身抗体可以 ICI 加剧了 irAE。在这个项目中，我们建议完善和验证基线 autoAb 生物标志物。使用来自两项大型辅助 ICI 临床试验（针对切除的 III/IV 期）的血清 (n=600) 进行 ICI 毒性特征黑色素瘤（目标 1）了解特定自身抗体与常见 irAE（例如结肠炎）的相关性。调查一些患者的自身免疫倾向，我们将比较 irAE 相关的自身抗体我们将使用我们的人源化 FcR 小鼠。确定 autoAb 和 irAE 之间因果关系的模型，重点关注结肠炎，并用于预防性抗 TNF-α 的临床前测试作为减轻 ICI 胃肠道 (GI) 毒性的策略（目标 2). 这些发现将为患者预防性抗 TNF-α（英夫利昔单抗）的生物标志物驱动的 II 期试验提供信息。接受 ICI 治疗的人有发生严重腹泻和结肠炎的高风险（目标 3）。我们的工作将通过验证强大的治疗前生物标志物来为个性化黑色素瘤治疗策略提供信息使婴儿能够优化 ICI 治疗方案并最大程度地减少患者接触严重 irAE 的风险。自身免疫对 irAE 发展的易感性，并确定预防性 TNF-α 阻断是否可以减轻在被确定为这些 irAE 高风险的患者中，ICI 会导致胃肠道毒性。