Predictive modeling of cutaneous immune checkpoint inhibitor toxicities

项目摘要/摘要 免疫检查点抑制剂(ICIS)已成为越来越多患者的标准护理 仅在美国，每年就有多达23万名患者有资格接受ICI治疗。尽管他们 疗效，ICIS与病态和潜在的致命毒性有关，称为免疫相关不良反应 事件(IrAE)。皮肤血管紧张素转换酶(IrAEs)是最常见的毒性反应，其发生率为20-40%。 到目前为止，文献中报道了40多种不同形态亚型的治疗患者。尽管这些 毒性的严重程度各不相同，它们对患者的生活质量造成相当大的负担，并可能导致 中断挽救生命的ICI治疗或依赖可能钝化抗肿瘤的全身免疫抑制 ICIS的影响。迫切需要了解这些不良反应是如何发生的以及为什么会发生并减少 他们的影响。这项研究将调查真实世界的流行病学、下游的临床影响和风险。 使用交叉验证的机构和人口水平的数据来确定这些毒性发展的因素。 我们的第一个目标是提出一项强有力的观察性研究，以确定皮疹与最强烈的 与ICI治疗的关系，这将反过来被用来确定临床风险因素的发展 这些事件及其下游结果。这一点尤其重要，因为来自临床试验的Cirae数据 ICIS主要是由非皮肤科医生记录的，导致皮肤病表型有限。此外， 目前缺乏关于CIRE的大规模数据，也没有关于什么的定义标准 构成皮肤免疫疗法的毒性，限制了这一领域的所有研究。我们将进一步调查 CirAEs对全身免疫抑制利用和生存的影响。 我们的第二个目标是使用组织样本确定与Cirae发育有关的种系。 从我们机构的ICI接受者那里收集的。许多自身免疫性疾病都有大量的生殖系风险变异 我们推测，人类白细胞抗原的变异也会影响循环脑脊髓炎的发生。我们的 初步数据表明，CirAEs患者更有可能是HLA-DR4携带者， 自身免疫易感性的多基因风险评分(PRSS)也与CirAEs显著相关。 我们机构正在进行的基因分型将使这些结果得到验证，并扩大我们的风险预测 用于识别在人类白细胞抗原区域内外的其他遗传变异的模型。 AIMS 1和AIMS 2的结果将被整合到临床和遗传风险分层的组合工具中 用于AIM 2c中的CIRAE开发。由于CirAEs是最早发生的ICI毒性，并且高度相关 随着非皮肤irAEs的发展，这种风险分层反过来将使临床医生能够优先考虑更多 为最不可能发生毒性的患者进行强化癌症治疗，并提供增强的 对发生这些事件风险最高的弱势人群进行监测。

Project Summary/Abstract Immune checkpoint inhibitors (ICIs) have become standard of care for an increasing number of malignancies with up to 230,000 patients eligible for ICI therapy annually in the US alone. Despite their efficacy, ICIs are associated with morbid and potentially fatal toxicities, known as immune-related adverse events (irAEs). Cutaneous irAEs (cirAEs) are the most frequently reported toxicities, occurring in 20-40% of all treated patients with over 40 distinct morphologic subtypes reported in literature to date. Though these toxicities vary in severity, they have a considerable burden on patient quality of life and may result in interruption of life-saving ICI therapy or reliance on systemic immunosuppression that may blunt the anti-tumor effect of ICIs. There is an urgent need to understand how and why these adverse reactions occur and reduce their impact. This study will investigate the real-world epidemiology, downstream clinical implications, and risk factors for the development of these toxicities using cross-validated institutional and population-level data. Our first aim proposes a robust observational study to identify cutaneous eruptions with the strongest associations with ICI therapy, which will, in turn, be used to identify clinical risk factors for the development of these events and their downstream outcomes. This is particularly important as cirAE data from clinical trials of ICIs was largely documented by non-dermatologists with resulting limited dermatologic phenotyping. Further, there is currently a lack of large-scale data on cirAEs and an absence of definitional standards for what constitutes a cutaneous immunotherapy toxicity, limiting all research in this field. We will further investigate the impact of cirAEs on systemic immunosuppression utilization and survival. Our second aim will identify germline associations for cirAE development using tissue samples collected from ICI recipients at our institutions. Many autoimmune diseases have germline risk variants of large effect in the HLA region and we hypothesize that HLA variation will also influence development of cirAEs. Our preliminary data has demonstrated that patients with cirAEs were more likely to be HLA-DR4 carriers and that polygenic risk scores (PRSs) for autoimmunity predisposition were also significantly associated with cirAEs. Ongoing genotyping at our institution will enable validation of these results and expansion of our risk prediction models to identify additional genetic variants within and outside the HLA region. Results from Aims 1 and 2 will be integrated into a combined clinical and genetic risk stratification tool for cirAE development in Aim 2c. Since cirAEs are the earliest ICI toxicities to occur and are highly correlated with development of non-cutaneous irAEs, this risk stratification will, in turn, enable clinicians to prioritize more intensive cancer therapies for patients least likely to develop toxicity as well as to provide enhanced surveillance of vulnerable populations at highest risk of developing these events.