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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）疗法已经改变了实体瘤的治疗。临床反应在范围内