(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：
10406245
负责人：
Kevan C Herold
金额：
$ 55.48万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406245
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.

概括检查点抑制剂（CPI）疗法极大地改善了以前癌症的治疗由于这些药物的预期生物活性，可以激活 T，因此被认为是棘手的。可以导致肿瘤破坏的细胞，这些新的自身免疫不良事件已经发生。不良事件发生在内分泌组织，包括甲状腺和胰腺β细胞。频繁的自身免疫性糖尿病已成为一种严重的不良事件，通常需要重症监护。有些人发生这些自身免疫事件以及为什么有些人受到保护的原因尚不清楚已知，但此信息可能会导致预防这些不良事件发生的方法。如果该提议是为了了解自身免疫的分子和细胞免疫学基础，那么它是客观的糖尿病和甲状腺疾病，并测试是否可以使用针对其具体情况的药物进行预防我们希望测试的假设是，在患有内分泌疾病的个体中进行 CPI 治疗。诱导病理性 T 细胞、B 细胞耐受性丧失和调节性 T 细胞功能失调。已经确定了那些做和做的人中自身抗原反应性效应 T 细胞和 Tregs 的表型差异此外，我们对自身反应性 B 细胞的分析表明 CPI 治疗。影响外周 B 细胞耐受检查点并导致自身反应性成熟频率增加我们计划使用 Seq-Well 单细胞对前瞻性随访的患者进行分析。治疗前至出现自身免疫性内分泌病时。是 HLA-A2 (~40%) 我们将使用细胞文库和 CyTOF 研究甲状腺和糖尿病反应性 CD8+ T 细胞并确定在抗原反应性细胞上发现的 T 细胞受体是否可以在我们还将确定 CPI 是否影响 CPI 的数量和功能。 Tregs 并具体讨论 CPI 是否导致 Tregs 产生病理性细胞因子。确定 CPI 是否会导致外周 B 细胞耐受失败的技术确定 B 细胞和 Tregs 变化之间的关系我们将收集有关自身反应性 T 的数据。和 B 细胞库，我们将其与原发性肿瘤的临床反应相关联。这些不良事件背后的免疫学机制表明了它们可能的作用方式我们将在 NOD 小鼠的抗 PD-L1 诱导糖尿病小鼠模型中进行测试。无论是通过低剂量的 IL-2 还是通过输注糖尿病来消除 B 细胞或增强 Tregs 因此，抗原特异性 Tregs 可以预防糖尿病的发生。这些严重的不良事件，确定最有可能发生这些事件的个人，并测试是否不干扰 CPI 抗肿瘤作用的疗法可用于预防它们。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prolonged Complete Response of Early Stage Primary Adenocarcinoma of the Lung to Nivolumab Monotherapy.

早期原发性肺腺癌对纳武单抗单药治疗的长期完全缓解。

DOI：
发表时间：
2021-01
期刊：
影响因子：
0
作者：
Unlu, Serhan;Grant, Michael J;Gettinger, Scott;Adeniran, Adebowale;Kluger, Harriet M
通讯作者：
Kluger, Harriet M

Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity.

通过心脏磁共振成像对免疫检查点抑制剂相关的心脏毒性进行左心室心肌应变和组织表征。

DOI：
发表时间：
2021
期刊：
影响因子：
3.7
作者：
Higgins, Angela Y;Arbune, Amit;Soufer, Aaron;Ragheb, Elio;Kwan, Jennifer M;Lamy, Jerome;Henry, Mariana;Cuomo, Jason R;Charifa, Ahmad;Gallegos, Cesia;Hull, Sarah;Coviello, Jessica Shank;Bader, Anna S;Peters, Dana C;Huber, Steffen;Mojibian, H
通讯作者：
Mojibian, H

Mycophenolate as Primary Treatment for Immune Checkpoint Inhibitor Induced Acute Kidney Injury in a Patient with Concurrent Immunotherapy-Associated Diabetes: A Case Report.

麦考酚酯作为免疫检查点抑制剂引起的并发免疫治疗相关糖尿病患者急性肾损伤的主要治疗：病例报告。