Identification of pathways to mitigate Immune-Related Adverse Events with Cancer Immunotherapy

确定通过癌症免疫治疗减轻免疫相关不良事件的途径

• 批准号: 10395923
• 负责人: JEFFREY A KERN
• 金额: $ 61.09万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395923
• 关键词: Address; Adrenal Cortex Hormones; Adverse event; Affect; Anti-Inflammatory Agents; Applications Grants; Autoimmune; Biological; Biological Assay; Biological Markers; Biological Products; Blood; Clinical; Cutaneous; Cytokine Activation; Dermatologic; Development; Dose; Early identification; Endocannabinoids; Event; Glucocorticoid Receptor; Goals; Guidelines; Homing; Immune; Immune Targeting; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immunology; In Vitro; Inflammatory; Interleukin-13; Interleukin-4; Interruption; Intervention; Knowledge; Lead; Leukotrienes; Link; Lipids; Maintenance; Malignant Neoplasms; Organ; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Prevention; Prostaglandins; Reaction; Registries; Resolution; Role; Sampling; Signal Pathway; Signal Transduction; Skin; Skin Manifestations; Steroids; T-Lymphocyte; TNF gene; Testing; Toxic effect; Urine; anti-CTLA4; anti-PD-L1; autoinflammatory; biobank; cancer immunotherapy; cancer therapy; clinical phenotype; cytokine; filaggrin; glucocorticoid receptor alpha; immune-related adverse events; immunoreaction; improved; improved outcome; lipidome; novel therapeutic intervention; predicting response; prospective; response; skin barrier; targeted treatment; translational approach

PROJECT SUMMARY / ABSTRACT: The emergence of immune checkpoint inhibitors (CPIs) has significantly improved outcomes for patients with a variety of malignancies. By blocking the inhibitory signaling pathways of T cells, CPIs are associated with a diverse spectrum of immune-related adverse events (irAEs). Immune-related cutaneous adverse events (ircAE) are the most frequent AE and may result in CPI dose interruption or discontinuation. Current guidelines recommend corticosteroids for the management of irAEs including those affecting skin. Yet ~25% of ircAEs are steroid unresponsive, and their use has revealed a negative effect on survival, underscoring the need for early identification of corticosteroid unresponsiveness and rational therapies. Although the underlying pathogenic mechanism of irAEs remain elusive, autoimmune and autoinflammatory reactions have a putative role in their development and maintenance. Thus, understanding the pathogenic events underlying irAEs are critical to their prevention and treatment. The underlying mechanisms of irAEs remain a significant knowledge gap that we will address in this proposal. Our Central Hypothesis is that patients with ircAEs have unique endotypes associated with polarized immune responses in the skin and blood, which results in corticosteroid responsive and unresponsiveness reactions that may require intervention with targeted immune pathway blockade. In addition, we hypothesize that specific ircAE skin manifestations are associated with unique immune dermatologic responses. Cutaneous irAEs give us a unique opportunity to understand the immune reaction in the involved end organ and systemically. We will test our central hypothesis through; Aim 1: Define and correlate ircAE phenotypes with their immune reaction endotype and response to toxicity- directed therapy. In this aim we hypothesize that ircAEs are associated with distinct, polarized immune endotypes that correlate with specific cutaneous phenotypes and predict response to available interventions (corticosteroids, biologics targeting inflammatory pathways). Aim 2: Identify skin and circulating lipid biomarkers which occur during and after ircAEs. This aim tests the hypothesis that distinct ircAE clinical phenotypes and their endotypes will manifest unique changes in the skin structural and circulatory signaling lipidome and suggest novel therapeutic strategies to mitigate ircAEs. Aim 3: Determine mechanisms associated with corticosteroid unresponsiveness in patients with ircAE. This aim tests the hypothesis that steroid unresponsiveness can be defined by understanding the major mechanistic pathways involved, and ultimately allow targeted therapy to resolve the ircAE. In this translational approach to understanding ircAEs, our goal is to define in patients, the mechanisms involved in ircAEs, activated polarized pathways, and advance our understanding of translational immunology as well as lead to actionable interventions to mitigate these devastating AEs that can limit cancer therapy.

项目总结/摘要： 免疫检查点抑制剂（CPI）的出现显着改善了具有免疫缺陷的患者的结局。 各种恶性肿瘤通过阻断T细胞的抑制性信号传导途径，CPI与T细胞的免疫抑制有关。 免疫相关不良事件（irAE）的多样性。免疫相关皮肤不良事件（ircAE） 是最常见的AE，可能导致CPI给药中断或停药。现行指南 建议使用皮质类固醇治疗irAE，包括影响皮肤的irAE。然而，约25%的ircAE是 类固醇无反应，使用它们对生存率有负面影响，强调需要早期 糖皮质激素无反应性的鉴别及合理治疗。尽管潜在的致病因素 irAE的机制仍然难以捉摸，自身免疫和自身炎症反应在其发病机制中具有假定的作用。 开发和维护。因此，了解irAE背后的致病事件对于其治疗至关重要。 预防和治疗。irAE的潜在机制仍然是一个重大的知识差距，我们将 在这个提案中。我们的中心假设是ircAE患者具有独特的内型 与皮肤和血液中的极化免疫反应相关，这导致皮质类固醇反应性 以及可能需要靶向免疫途径阻断干预的无反应性反应。在 此外，我们假设特异性的ircAE皮肤表现与独特的免疫皮肤病学相关， 应答皮肤irAE为我们提供了一个独特的机会，以了解免疫反应，在涉及 终末器官和系统性的。我们将通过以下方式来检验我们的核心假设： 目的1：定义ircAE表型并将其与免疫反应内型和毒性反应相关- 定向治疗在这个目标中，我们假设ircAE与不同的极化免疫相关， 与特定皮肤表型相关并预测对可用干预措施的反应的内型 （皮质类固醇，靶向炎症通路的生物制剂）。 目的2：确定在ircAE期间和之后发生的皮肤和循环脂质生物标志物。这一目标考验着 不同的ircAE临床表型及其内在型将在皮肤中表现出独特变化的假设 结构和循环信号脂质组，并提出新的治疗策略，以减轻ircAE。 目的3：确定与ircAE患者皮质类固醇无反应相关的机制。这一目标 测试类固醇无反应性的假设可以通过理解主要的机制来定义， 参与的途径，并最终允许靶向治疗解决ircAE。 在这种理解ircAE的转化方法中，我们的目标是在患者中定义相关机制， 在ircAE中，激活了极化途径，并促进了我们对翻译免疫学的理解， 导致可行的干预措施，以减轻这些可能限制癌症治疗的破坏性AE。