(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）疗法已大大改善了以前曾经是的癌症的治疗被认为是棘手的。由于这些药物的预期生物学活性，这可以激活T 可能导致肿瘤破坏的细胞，发生了新的自身免疫性不良事件。这些的主要目标不良事件是胰腺中包括甲状腺和β细胞在内的内分泌组织。甲状腺炎是经常出现自身免疫性糖尿病是一个严重的不良事件，通常需要重症监护。某些人开发这些自身免疫事件的原因以及为什么有些受保护的原因不是已知但是这些信息可能导致防止这些不良事件发生的方法。总体目的，如果该建议是要了解自身免疫的分子和细胞免疫基础糖尿病和甲状腺疾病，并测试是否可以用特定的药物来预防它们动作。我们希望检验的假设是，在发展内分泌病治疗的个体中诱导病理T细胞，B细胞耐受性的丧失和功能障碍调节T细胞。我们的初步数据已经确定了自身抗原反应性效应t细胞和Tregs的表型差异不发展内分泌病。此外，我们对自动反应性B细胞的分析表明CPI治疗影响外周B细胞耐受性检查点，并导致自动反应性成熟的频率增加幼稚的B细胞。我们计划使用SEQ-WELL单细胞进行分析在治疗之前，他们何时出现自身免疫性内分泌病。在个人子组中是HLA-A2（〜40％），我们将研究甲状腺和糖尿病与细胞库的反应性CD8+ T细胞和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治疗和亚群。我们还将确定CPI是否会影响 Tregs并特别解决CPI是否导致Treg产生病理细胞因子。我们将使用确定CPI是否诱导周围B细胞耐受性和确定B细胞和Tregs的变化之间的关系。我们将收集有关自动反应性T的数据和B细胞库，我们将与对原发性肿瘤的临床反应相关。最后，我们对这些不良事件的基础的免疫机制提出了它们可能是它们的方式防止，我们将在NOD小鼠的抗PD-L1诱导糖尿病的鼠模型中进行测试。我们将测试无论是通过低剂量的IL-2还是通过输注糖尿病抗原特异性Treg可以预防糖尿病发作。因此，这些研究将阐明这些严重的不良事件，确定对这些事件最大风险的个人，并测试是否不干扰CPI的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）

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

DOI：
发表时间：
2021-01
期刊：
Clinical oncology, case reports
影响因子：
0
作者：
Jessel S;Austin M;Kluger HM
通讯作者：
Kluger HM

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

DOI：
10.1371/journal.pone.0246764
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Higgins AY;Arbune A;Soufer A;Ragheb E;Kwan JM;Lamy J;Henry M;Cuomo JR;Charifa A;Gallegos C;Hull S;Coviello JS;Bader AS;Peters DC;Huber S;Mojibian HR;Sinusas AJ;Kluger H;Baldassarre LA
通讯作者：
Baldassarre LA

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