Multiplexed Bioassay for Checkpoint Inhibitor Autoimmunity

检查点抑制剂（CPI）疗法在人类癌症中的出现极大地改变了癌症的前景。 近年来的治疗策略。以前，癌症的治疗方法基本无效， 预后，如黑色素瘤，经历了显着的进步，患者能够延长生存 和/或无进展疾病。在肿瘤微环境中，许多免疫抑制因子 分子过表达，包括CTLA-4，PD-1及其配体PD-L1。简单地说，抑制这些 免疫抑制途径导致"耗尽的"细胞毒性T细胞和辅助性T细胞的再活化， 肿瘤的后续攻击。然而，接受CPI治疗的患者经历了各种不良反应， 免疫介导的不良事件（irAE）的副作用，许多导致显著的发病率， 平衡自身免疫和癌症管理的不确定性。这些不良事件 (of 1 - 5级）包括结肠炎、肺炎、神经病、内分泌病、肾炎、皮炎和关节炎。 据报道，超过80%的CPI治疗患者将经历某种形式的irAE。作为数字的 接受CPI治疗的患者增加，加上在联合治疗中使用CPI以及 随着新一代CPI的开发，irAE的治疗将使这些患者的医疗护理复杂化。 本提案的简单目标是开发基于Luminex的关键蛋白质生物标志物的生物测定 CPI患者在自身免疫综合征出现之前和出现时都会引发自身抗体 起来。一个多路复用的Luminex系统可以检测多达50个生物标志物， 生物标志物可能出现在CPI治疗的未来。该项目由一名负责领导CLIA的PI加强 耶鲁大学医学系认证的诊断实验室，与 内科肿瘤学，以及接受CPI治疗的患者和 自发性自身免疫性疾病患者。I期研究将开发和执行早期特异性 与生物标志物面板的研究，而II期研究将扩大到包括筛选更大的 使用特定CPI类型的患者队列以及稳健、灵敏和特异的生物测定系统。

The advent of checkpoint inhibitor (CPI) therapy in human cancer has dramatically changed the landscape of treatment strategies in recent years. Previously, cancers with largely ineffective therapeutics and a poor prognosis, such as melanoma, have experienced significant advances of patients able to extend survival and/or progression free disease. Within the tumor microenvironment, a number of immunosuppressive molecules are overexpressed, including CTLA-4, PD-1 and its ligand PD-L1. Simply put, inhibiting these immunosuppressive pathways causes the reactivation of ‘exhausted’ cytotoxic and helper T cells and subsequent attack of the tumor. However, patients treated with CPIs have experienced a variety of untoward side effects of immune mediated adverse events (irAEs), many leading to significant morbidity and uncertainties in balancing the management of both the autoimmunity and the cancer. These adverse events (of grades 1-5) include colitis, pneumonitis, neuropathies, endocrinopathies, nephritis, dermatitis, and arthritis. It is reported that upwards of 80% of CPI treated patient will experience some form of irAE. As the numbers of patients treated with CPIs increases, coupled with the use of CPIs in combination therapies as well as the development of new generations of CPIs, the treatment of irAEs will complicate medical care in these patients. The simple goal of the present proposal is to develop a Luminex based bioassay of the key protein biomarkers to which CPI patients elicit autoantibodies both prior to, and as the appearance of autoimmune syndromes arise. A multiplexed Luminex system can detect as many as 50 biomarkers and be simply modified as new biomarkers may emerge in the future of CPI therapy. The project is strengthened by a PI who directs a CLIA certified diagnostic laboratory in the Department of Medicine at Yale University with close ties to the Section of Medical Oncology and with an existing serum library collection of both patients treated with CPIs and of patients with spontaneous autoimmune disease. Phase I studies will develop and perform early specificity studies with the panel of biomarkers while phase II studies will be expanded to include a screening of larger cohorts of patients on specific CPI types as well as a robust, sensitive and specific bioassay system.