Finding the optimal balance of immunotherapy efficacy and toxicity.

U 01摘要 尽管对癌症免疫疗法进行了广泛的研究，但免疫相关不良事件（irAE） 仍然是一个关键的和知之甚少的问题。为了满足这一关键需求，我们已经组建了一个 多学科研究团队，具有广泛的相关专业知识。该提案的共同PI有 癌症免疫治疗、免疫学、检测开发和生物信息学方面的专业知识。一起我们 已经收集了一个约400名接受ICI治疗的癌症患者的队列，收集纵向治疗，疗效， 和毒性数据，以及治疗前基线、整个治疗期间和 毒性在我们的真实世界数据集中，超过10%的病例有自身免疫性疾病史， 深入了解ICI在广泛排除在临床试验之外但常规接受以下治疗的人群中的使用情况： 这些治疗都是违规的我们的高质量临床数据注释-没有相关研究 没有什么意义-解决了irAE可能在ICI开始后几个月发生的现实， 检测和表征比常规化疗或分子靶向化疗的毒性更复杂 治疗通过现有的资助机制，我们已经完成了自身抗体，细胞因子， 在这些情况下进行基因和功能分析。但是，我们目前没有资源 对这些不同的实验室和临床数据进行全面、综合的分析。的首要目标 U 01的建议是要最终确定ICI有效性和毒性之间的最佳平衡， 鉴定可用于选择患者、治疗类型和持续时间的一组生物标志物，和 临床监测我们将通过测定细胞免疫、综合数据 分析和临床验证。我们有三个目的：（1）确定患者的细胞免疫 发生irAE和/或从ICI获得有益反应。我们将进行大量细胞计数 在多个时间点进行细胞时间间隔（CyTOF）和T细胞受体测序。(2)确定遗传、体液和 与irAE相关的细胞因子和/或ICI的有益反应。我们会建立一个数据库 整合和分析CyTOF和T细胞受体测序数据与临床疗效和毒性 数据，以及来自通过其他机制已经完成的测定的数据。(3)执行分析 和新兴生物标志物的临床验证。我们将应用最好的分类表型出现 从我们全面综合的数据分析到我们现有队列的患者测试集， 最终鉴定具有临床应用潜力的生物标志物的子集。总之，这些目标 直接解决FOA的目的，即降低irAE的发生率和/或严重程度，同时保留抗 肿瘤疗效

U01 Abstract Despite extensive research into cancer immunotherapy, immune-related adverse events (irAE) remain a critical and poorly understood issue. To address this critical need, we have assembled a multidisciplinary research team with broad and relevant expertise. The co-PIs of this proposal have expertise in cancer immunotherapy, immunology, assay development, and bioinformatics. Together, we have assembled a cohort of ~400 cancer patients treated with ICI, collecting longitudinal treatment, efficacy, and toxicity data, as well as blood samples at pre-treatment baseline, throughout therapy, and at time of toxicity. In our real-world data set, over 10 percent of cases have a history of autoimmune disease, providing insight into use of ICI in a population widely excluded from clinical trials yet routinely treated with these therapies off protocol. Our high-quality clinical data annotation—without which correlative studies have little meaning—addresses the reality that irAE may occur months after ICI initiation and are far more complex to detect and characterize than toxicities of conventional chemotherapy or molecularly targeted therapies. Through existing funding mechanisms, we have already completed autoantibody, cytokine, genetic, and functional assays in these cases. However, we do not currently have resources for comprehensive, integrated analysis of these diverse laboratory and clinical data. The overarching goal of this U01 proposal is to determine the optimal balance between ICI efficacy and toxicity, ultimately identifying a set of biomarkers useful for selection of patients, treatment type and duration, and clinical monitoring. We will achieve this through determination of cellular immunity, comprehensive data analysis, and clinical validation. We have three Aims: (1) Determine cellular immunity in patients experiencing irAE and/or achieving beneficial responses from ICI. We will perform mass cytometry (CyTOF) and T-cell receptor sequencing at multiple time-points. (2) Determine genetic, humoral, and cellular factors associated with irAE and/or beneficial responses from ICI. We will develop a database to integrate and analyze the CyTOF and T-cell receptor sequencing data with clinical efficacy and toxicity data, as well as data from the assays already completed through other mechanisms. (3) Perform analytical and clinical validation of emerging biomarkers. We will apply the best classifying phenotypes emerging from our comprehensive and integrated data analysis to a test set of patients from our existing cohort, eventually identifying a subset of biomarkers with potential for clinical application. Together, these Aims directly address the FOA purpose of reducing the incidence and/or severity of irAE while retaining anti- tumor efficacy.