Project 3

项目3

• 批准号: 10200703
• 负责人: MICHELLE KROGSGAARD
• 金额: $ 28.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10200703
• 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; 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

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概要 免疫检查点抑制剂改变了黑色素瘤治疗，产生持久的反应，延长 存活率和临床获益。此外，它们延迟复发并延长 在辅助性黑色素瘤环境中的存活率，并且在一系列不同的癌症类型中也显示出功效。 然而，免疫检查点抑制（ICI）疗法也可伴随免疫相关不良反应。 影响多个器官、导致显著发病率和需要免疫抑制的事件（irAE），或 停止ICI治疗。迫切需要确定将发生重度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，以减轻 更好地控制毒性。虽然人们对识别标记物来预测对 ICI，没有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。我们的目标 该项目旨在开发一种预测工具，使临床医生能够最大限度地减少患者对严重 毒性，同时最大化ICI的临床获益。 我们假设黑色素瘤患者的一个子集有基线，亚临床自身免疫性 易感性，其特征是特异性预先存在的自身抗体（autoAb），可以预测和 加剧ICI治疗的毒性发展。我们已在基线中识别出autoAb特征 在用ICI治疗的黑色素瘤患者中预测严重免疫毒性的（治疗前）血清（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autoAb可以 加重ICI引起的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临床试验的血清（n=600）对III/IV期切除的ICI毒性特征 黑色素瘤（Aim 1）。为了了解特异性autoAb与常见irAE的相关性（例如，结肠炎）和 为了研究某些患者的自身免疫易感性，我们将比较irAE相关的自身抗体与 来自炎症性肠病患者和正常捐赠者。我们将使用我们的人源化Fc受体小鼠 确定autoAb和irAE之间因果关系的模型，重点关注结肠炎， 预防性抗TNF-α作为减轻ICI胃肠道（GI）毒性的策略的临床前试验（Aim 2）。这些发现将为一项生物标志物驱动的II期临床试验提供信息， 接受ICI治疗的患者中，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一个强大的治疗前生物标志物来告知个性化的黑色素瘤治疗策略 使临床医生能够优化ICI方案，并最大限度地减少患者暴露于重度irAE。我们都将确认 自身免疫易感性irAE的发展，并建立预防性TNF-α阻断是否减轻 在确定为这些irAE高风险的患者中，ICI发生GI毒性。