Multiplexed Bioassay for Checkpoint Inhibitor Autoimmunity

检查点抑制剂自身免疫的多重生物测定

• 批准号: 9909591
• 负责人: Mark J Mamula
• 金额: $ 29.89万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-09 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909591
• 关键词: Adverse event; American; Antibodies; Appearance; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological Assay; Biological Markers; Blinded; CTLA4 gene; Cancer Patient; Caring; Celiac Disease; Cessation of life; Clinical; Clinical Laboratory Improvement Amendments; Colitis; Collection; Combined Modality Therapy; Complication; Coupled; Data; Dermatitis; Development; Diabetes Mellitus; Diagnostic; Disease; Enzyme-Linked Immunosorbent Assay; Equilibrium; Evaluation; Event; Future; Generations; Goals; Helper-Inducer T-Lymphocyte; Hospitalization; Human; Hypothyroidism; Immune; Immune Targeting; Immune checkpoint inhibitor; Immunologics; Immunotherapy; Incidence; Individual; Insulin-Dependent Diabetes Mellitus; Investigation; Laboratories; Lead; Letters; Libraries; Ligands; Link; Lupus; Malignant Neoplasms; Measures; Medical; Medical Oncology; Medicine; Morbidity - disease rate; Nephritis; Neuropathy; Outcome; PD-1/PD-L1; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Population Control; Proteins; Pulmonary Inflammation; Renal Cell Carcinoma; Reporting; Rheumatoid Arthritis; Rheumatology; Risk; Sampling; Self Tolerance; Sensitivity and Specificity; Serum; Source; Specificity; Standardization; Symptoms; Syndrome; System; Therapeutic; Thyroiditis; Time; Uncertainty; Universities; Validation; Work; Yale Cancer Center; anti-CTLA-4 therapy; anti-CTLA4; anti-PD-L1 therapy; autoreactive T cell; base; biobank; biomarker development; biomarker panel; cancer therapy; checkpoint therapy; clinical care; cohort; college; cytotoxic; exhaust; experience; immune activation; immune-related adverse events; improved; melanoma; mortality; outcome forecast; overexpression; phase 1 study; phase 2 study; prevent; programmed cell death ligand 1; programmed cell death protein 1; prospective; protein biomarkers; screening; side effect; skin disorder; stem; success; targeted treatment; tool; treatment strategy; tumor; tumor microenvironment

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.

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治疗的格局 近年来的治疗策略。此前，癌症的治疗方法基本上无效且治疗效果不佳 预后，例如黑色素瘤，已经取得了显着进展，患者能够延长生存期 和/或疾病无进展。在肿瘤微环境中，许多免疫抑制因子 分子过度表达，包括 CTLA-4、PD-1 及其配体 PD-L1。简单来说就是抑制这些 免疫抑制途径导致“耗尽”的细胞毒性和辅助性 T 细胞重新激活， 随后肿瘤的攻击。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，许多会导致严重的发病率和 平衡自身免疫和癌症管理的不确定性。这些不良事件 （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 治疗患者会经历某种形式的 irAE。作为数量 随着 CPI 联合疗法的使用以及 CPI 治疗的患者数量的增加 随着新一代 CPI 的开发，irAE 的治疗将使这些患者的医疗护理变得复杂。 本提案的简单目标是开发一种基于 Luminex 的关键蛋白质生物标志物生物测定方法 CPI 患者在自身免疫综合征出现之前和出现时都会产生自身抗体 出现。多重 Luminex 系统可以检测多达 50 种生物标志物，并且可以简单地修改为新的 生物标志物可能会在未来的 CPI 治疗中出现。该项目由指导 CLIA 的 PI 加强 耶鲁大学医学系经过认证的诊断实验室，与该科有密切联系 肿瘤内科和现有的血清库收集了接受 CPI 治疗的患者和 患有自发性自身免疫性疾病的患者。第一阶段研究将开发并执行早期特异性 生物标志物组的研究，而 II 期研究将扩大到包括更大范围的筛选 特定 CPI 类型的患者队列以及强大、灵敏和特定的生物测定系统。