Project 3

项目3摘要 免疫检查点抑制剂改变了黑色素瘤的治疗，产生了持久的反应，延长了 存活率和临床受益的患者占很大比例。此外，它们可以延缓复发并延长 在辅助性黑色素瘤环境中的存活率，并在一系列不同类型的癌症中也显示出疗效。 然而，免疫检查点抑制(ICI)治疗也可能伴随免疫相关的不良反应 影响多个器官的事件(IrAE)，导致显著的发病率，并需要免疫抑制或 停止ICI治疗。迫切需要确定哪些患者将从以下方面发展为严重的irAEs ICI。这将使我们能够优化治疗选择和排序，证明预防战略的合理性 毒性，并更好地管理毒性。虽然人们对识别预测反应的标志物有浓厚的兴趣 ICI，没有任何治疗前生物标记物工具可以预测任何癌症类型与ICI相关的irAEs。我们的目标是 项目是开发一种预测工具，使临床医生能够最大限度地减少患者暴露在严重的 毒性，同时最大限度地提高ICI的临床效益。 我们假设有一部分黑色素瘤患者有一个基线的亚临床自身免疫。 易感性，特征是特定的预先存在的自身抗体(AutoAbbs)可以预测和 加剧ICI治疗的毒性发展。我们已经确认了基线中的自体抗体签名 (治疗前)血清，预测ICI治疗的黑色素瘤患者的严重免疫毒性(AUC&GT；0.95)。 使用人源化的小鼠模型，我们发现来自黑色素瘤患者基线血清的自身抗体可以 加重来自ICI的irAEs。在这个项目中，我们建议提炼和验证基线AutoAb生物标记物 切除III/IV期的两个大型ICI临床试验的血清(n=600)对ICI毒性的特征 黑色素瘤(目标1)。了解特定的自体抗体与常见的irAEs(如结肠炎)的相关性 研究一些患者的自身免疫易感性，我们将比较IRAE相关的自身抗体和 来自炎症性肠病患者和正常捐赠者。我们将使用我们的人性化FCR鼠标 确定自体抗体和irAEs之间因果关系的模型，重点是结肠炎，以及 预防性抗肿瘤坏死因子-作为减轻脑梗塞胃肠道毒性的临床前试验(AIM 2)。这些发现将为生物标志物驱动的预防性抗肿瘤坏死因子-(英夫利昔单抗)在患者中的II期试验提供信息 接受严重腹泻和结肠炎高危人群的ICI治疗(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为个性化的黑色素瘤治疗策略提供信息 使临床医生能够优化ICI方案，最大限度地减少患者暴露于严重的irAEs。我们都会认同 自身免疫对IRAE发生的易感性及预防性阻断肿瘤坏死因子-是否可缓解 ICI对被确认为这些irAEs高危患者的胃肠道毒性的发展。

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.