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(8) Mechanisms of autoimmune endocrine diseases in patients receiving checkpoint inhibitors

(8)检查点抑制剂患者发生自身免疫内分泌疾病的机制

基本信息

批准号：
10152527
负责人：
Kevan C Herold
金额：
$ 58.01万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152527
关键词：
Addison&apos s disease Address Adverse event Affect Aftercare Antigens Autoantigens Autoimmune Autoimmune Diabetes Autoimmune Process Autoimmune Responses B cell repertoire B-Lymphocytes Beta Cell Biological Markers Blocking Antibodies Blood CD8-Positive T-Lymphocytes CTLA4 gene Cells Clinical Data Defect Development Diabetes Mellitus Disease Dose Endocrine Endocrine System Diseases Event Failure Frequencies Functional disorder HLA-A2 Antigen Hashimoto Disease Immune Immune checkpoint inhibitor Immune response Immunologics Immunologist Inbred NOD Mice Individual Infusion procedures Insulin-Dependent Diabetes Mellitus Intensive Care Interleukin-2 Intervention Knowledge Lead Libraries Life Life Expectancy Ligands Malignant Neoplasms Malignant neoplasm of lung Modeling Modification Molecular Monoclonal Antibodies Morbidity - disease rate Oncologist PD-1 inhibitors Pancreas Pathologic Patients Peripheral Pharmaceutical Preparations Phenotype Pre-Clinical Model Primary Neoplasm Regimen Regulatory T-Lymphocyte Renal Cell Carcinoma Reporting Risk Sampling Serious Adverse Event Subgroup T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Thyroid Diseases Thyroid Gland Thyroiditis Time Tissues anti-PD-1 anti-PD-L1 anti-PD-L1 antibodies anti-PD1 antibodies antitumor effect autoimmune endocrine disorder autoreactive B cell autoreactive T cell autoreactivity biomarker development cancer therapy checkpoint therapy chemotherapy cytokine diabetogenic drug biological activity effector T cell immune-related adverse events improved ipilimumab melanoma mouse model prevent programmed cell death protein 1 prospective response sample collection tool transcriptome transcriptome sequencing treatment strategy tumor

项目摘要

Summary Checkpoint inhibitor (CPI) therapy has greatly improved the treatment of cancers that had previously been considered intractable. As a result of the intended biologic activity of these drugs, which enable activation of T cells that can cause tumor destruction, new autoimmune adverse events have occurred. Major targets of these adverse events have been endocrine tissues including thyroid and beta cells in the pancreas. Thyroiditis is frequent and autoimmune diabetes has emerged as a serious adverse event often requiring intensive care. The reasons why some individuals develop these autoimmune events and why some are protected are not known but this information may lead to ways of preventing the occurrence of these adverse events. The overall objective if this proposal is to understand the molecular and cellular immunologic basis for autoimmune diabetes and thyroid disease and to test whether they can be prevented with agents that are specific in their actions. The hypothesis that we wish to test is that in individuals who develop endocrinopathies CPI therapy induces pathologic T cells, loss of B cell tolerance, and dysfunctional regulatory T cells. Our preliminary data has identified phenotypic differences in autoantigen reactive effector T cells and Tregs in those who do and do not develop endocrinopathies. In addition, our analysis of autoreactive B cells suggests that CPI therapy affects peripheral B cell tolerance checkpoints and results in an increased frequency of autoreactive mature naïve B cells. We plan to analyze, using Seq-Well single cells in patients who are followed prospectively from before treatment to when they present with autoimmune endocrinopathies. In the subgroup of individuals who are HLA-A2 (~40%) we will study thyroid and diabetes reactive CD8+ T cells with cellular libraries and CyTOF and determine whether the T cell receptors that are found on the antigen reactive cells can be detected prior to treatment and in which subpopulation. We will also determine whether CPIs affect the number and function of Tregs and address specifically whether the CPI causes the Tregs to produce pathologic cytokines. We will use established techniques to determine whether the CPIs induce a failure of peripheral B cell tolerance and identify the relationship between changes in B cells and Tregs. We will be collecting data on the autoreactive T and B cell repertoire that we will correlate with clinical responses to the primary tumors. Finally, our studies of the immunologic mechanisms that underlie these adverse events suggest ways in which they may be prevented, which we will test in a murine model of anti-PD-L1 induced diabetes in NOD mice. We will test whether B cell depletion or enhancement of Tregs, either by low doses of IL-2 or by infusion of diabetes antigen specific Tregs can prevent diabetes onset. These studies therefore, will elucidate the mechanisms of these serious adverse events, identify individuals who are at greatest risk for these events, and test whether therapies that do not interfere with the anti-tumor effects of the CPIs can be used to prevent them.

总结