Novel diagnostics for autoimmunity from checkpoint inhibitor immune therapy

检查点抑制剂免疫治疗的自身免疫新诊断

基本信息

批准号：
9466612
负责人：
Kevan C Herold
金额：
$ 29.98万
依托单位：
L2 DIAGNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9466612
关键词：
Address Adrenal Glands Adrenal gland hypofunction Adverse effects Adverse event Age Autoimmune Process Autoimmunity Beta Cell Biological Assay Biological Markers Blood Circulation Cancer Patient Catalytic Domain Cell Death Cell physiology Cells Clinical Colitis Cytotoxic T-Lymphocyte-Associated Protein 4 DNA DNA Methylation Detection Development Diabetes Mellitus Diagnosis Diagnostic Diagnostic tests Disease Elderly Endocrine Endocrine Glands Epigenetic Process Event G6PC2 gene Genes Goals Hospitalization Hyperglycemia Immune Immune checkpoint inhibitor Immunotherapy Individual Insulin Insulin-Dependent Diabetes Mellitus Intensive Care Lead Ligands Malignant Neoplasms Measurement Measures Medical Metabolic Metabolic syndrome Methods Monitor Morbidity - disease rate Nested PCR Non-Insulin-Dependent Diabetes Mellitus Non-Small-Cell Lung Carcinoma Organ Outcome PDCD1LG1 gene Patients Pattern Phase Pituitary Gland Prevention Reaction Reporting Risk Sampling Serum Solid Neoplasm Testing Thyroiditis Time Tissues Work adverse outcome base biobank bisulfite bisulfite sequencing blood glucose regulation cancer therapy cell killing cell type clinical care design digital experience glucose-6-phosphatase hormone deficiency immune activation immunoregulation improved in vivo inhibitor/antagonist islet killings melanoma methylation biomarker methylation pattern novel novel diagnostics prevent prospective response sample collection stem success tool tumor

项目摘要

Checkpoint inhibitor (CPI) therapy has transformed treatment of solid tumors. Clinical responses in the range of 20-25%, with prolonged survival, have been reported for tumors, such as malignant melanoma and non- small cell lung cancer, that previously had poor response rates and dismal prognoses. Current therapies block PD-1/PD-L1 and CTLA-4, and there are other targets being developed such as LAG3. However, these immune-based therapies can lead to adverse events. Unrestricted immune activation leads to autoimmunity, in particular endocrinopathies including thyroiditis, hypophysitis, and adrenalitis. We first reported the development of ketosis prone diabetes in elderly individuals treated with inhibitors of the PD-1/PD-L1 axis, and subsequently other studies have identified hyperglycemia as a consequence of CPI therapy with PD-1/PD-L1 antagonists. These hormone deficiencies, however, can result in considerable morbidity and prolonged hospitalization. Therefore, identifying individuals before they present with metabolic syndromes may enable the prevention of morbidity associated with the adverse effects of immune therapy and even open the possibility of selective immune modulation to prevent this occurrence in those at risk. To address this gap we developed assays to measure β cell death in serum of patients, based on the principle that dying cells release fragments of DNA into the circulation with cell-specific epigenetic patterns. Our preliminary studies from patients with cancers who were treated with CPIs indicated that this measurement may identify individuals who will develop diabetes prior to its clinical onset. Building upon this success, we propose to develop methylation marker specific assays for detecting adrenal and pituitary tissue damage and to further study changes in β cell derived DNA in patients. A recent review has shown that hypophysitis and adrenal insufficiency may be found in greater than 16% of individuals treated with anti-CTLA-4 mAb and in more than 5% of patients treated with anti-PD-1/PD-L1 blockade. In addition, endocrinopathies such as pituitary or adrenal insufficiency are difficult to diagnose without dynamic endocrine testing, which can only identify the insufficiency after it has led to organ destruction. Our experience with the analysis of the insulin gene and recently the IGRP gene for detection of β cell death has shown our ability to work with this approach and to use it to find clinically meaningful outcomes. These assays will fulfill an important unmet medical need: to identify patients who are developing endocrine complications from immunotherapy.

检查点抑制剂（CPI）疗法改变了实体瘤的临床反应。据报道，20-25% 的肿瘤（如恶性黑色素瘤和非黑色素瘤）的生存期延长。小细胞肺癌，以前的反应率很差，目前的治疗方法也很糟糕。 PD-1/PD-L1 和 CTLA-4，还有其他正在开发的靶标，例如 LAG3。基于免疫的疗法可能会导致不良事件，从而导致自身免疫。特别是内分泌疾病，包括甲状腺炎、垂体炎和肾上腺炎。使用 PD-1/PD-L1 轴抑制剂治疗的老年人出现酮症倾向糖尿病，以及随后的其他研究已确定高血糖是使用 PD-1/PD-L1 进行 CPI 治疗的结果然而，这些激素缺乏会导致相当大的发病率和长期的发病率。因此，在患者出现代谢综合征之前对其进行识别可能有助于预防和治疗。预防与免疫治疗的不良反应相关的发病率，甚至开启了以下可能性：为了解决这一问题，我们开发了选择性免疫调节来防止高危人群发生这种情况。基于垂死细胞释放碎片的原理来测量患者血清中 β 细胞死亡的测定我们对患者进行的初步研究表明，DNA 进入循环系统具有细胞特异性表观遗传模式。接受 CPI 治疗的癌症表明，这种测量可以识别将发展为癌症的个体基于这一成功，我们建议开发甲基化标记物。用于检测肾上腺和垂体组织损伤并进一步研究 β 细胞来源变化的特异性测定最近的一项检查显示，患者可能存在垂体炎和肾上腺功能不全。超过 16% 的接受抗 CTLA-4 mAb 治疗的个体以及超过 5% 的接受 CTLA-4 mAb 治疗的患者此外，垂体或肾上腺功能不全等内分泌疾病也很难治疗。无需进行动态内分泌检测即可诊断，动态内分泌检测只能在导致器官衰竭后才能确定我们在分析胰岛素基因和最近用于检测 β 的 IGRP 基因方面的经验。细胞死亡表明我们有能力使用这种方法并利用它来寻找具有临床意义的结果。这些测定将满足一个重要的未满足的医疗需求：识别正在发展内分泌的患者免疫治疗的并发症。