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

项目摘要/摘要： 免疫检查点抑制剂(CPIs)的出现显著改善了慢性粒细胞白血病患者的预后。 各种恶性肿瘤。通过阻断T细胞的抑制性信号通路，CPIs与 各种与免疫相关的不良事件(IrAEs)。免疫相关皮肤不良事件(IrcAE) 是最常见的不良反应，可能导致CPI剂量中断或停用。当前指导方针 推荐使用皮质类固醇治疗irAEs，包括那些影响皮肤的。然而，约25%的ircAE是 类固醇没有反应，而且它们的使用已经揭示了对生存的负面影响，强调了早期 皮质类固醇无反应的鉴定和合理的治疗。尽管潜在的致病因素 IrAEs的机制仍不清楚，自身免疫和自体炎症反应在其 开发和维护。因此，了解irAEs背后的致病事件对于它们的 预防和治疗。IrAEs的潜在机制仍然是我们将 在本提案中发言。我们的中心假设是ircAEs患者有独特的内型 与皮肤和血液中的极化免疫反应有关，这导致皮质类固醇反应 以及可能需要通过靶向免疫途径阻断进行干预的无反应反应。在……里面 此外，我们假设特殊的ircae皮肤表现与独特的免疫性皮肤病有关。 回应。皮肤irAEs给了我们一个独特的机会来了解受累的免疫反应。 结束器官和系统。我们将通过以下方式测试我们的中心假设： 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联。 定向治疗。在这个目的中，我们假设ircAEs与截然不同的、极化的免疫有关。 与特定皮肤表型相关的内型并预测对可用干预措施的反应 (皮质类固醇，针对炎症途径的生物制品)。 目的2：确定ircAEs术中和术后的皮肤和循环脂质生物标志物。这一目标考验着 假设不同的ircae临床表型及其内型将在皮肤中表现出独特的变化 结构和循环信号脂体，并建议新的治疗策略，以减轻ircAEs。 目的3：确定IRcAE患者糖皮质激素无反应的相关机制。这一目标 测试了类固醇无反应可以通过理解主要机制来定义的假设 最终允许靶向治疗来解决虹膜腔隙栓塞。 在这种理解ircAEs的翻译方法中，我们的目标是定义患者体内涉及的机制 在ircAEs中，激活极化的通路，并促进我们对翻译免疫学以及 导致可操作的干预措施，以减轻这些破坏性的不良反应，可能会限制癌症治疗。

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.