NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY

免疫治疗引起的自身免疫性疾病的新型体液和细胞生物标志物

基本信息

批准号：
10593224
负责人：
Hyun-Sung Lee
金额：
$ 24.01万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593224
关键词：
Addison&apos s disease Adrenal Cortex Adverse event Affect Antibodies Area Autoantibodies Autoimmune Autoimmune Diabetes Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Markers Blocking Antibodies CD8B1 gene COVID-19 pandemic CTLA4 gene Case Study Cells Circulation Clinical Clinical Trials Clonal Expansion Complex Coupled Cytometry Data Development Diabetes Mellitus Diabetic Ketoacidosis Disease Disease remission Early identification Early treatment Endocrine Endocrine System Diseases Endocrinology Enzymes Epitopes Extracellular Domain Gene Expression Histocompatibility Antigens Class II Human Image Immune Immune checkpoint inhibitor Immunity Immunologic Factors Immunologics Immunotherapy Inflammatory Insulin-Dependent Diabetes Mellitus Investigation Life Ligands Malignant Neoplasms Malignant Pleural Mesothelioma Mediating Medicine Memory Molecular Monoclonal Antibodies Neoadjuvant Therapy Neurosecretory Systems Oncology Outcome Pancreatitis Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Phenotype Pilot Projects Population Production Reporting Research Resectable Severity of illness Solid Neoplasm Steroid 21-Monooxygenase Syndrome T-Lymphocyte TP53 gene Testing Therapeutic Intervention Thyroid Diseases Time Toxic effect Variant Visit autoimmune thyroid disease autoreactive T cell body system cancer immunotherapy checkpoint receptors checkpoint therapy college common treatment follow-up health care delivery high dimensionality immune checkpoint blockade immune-related adverse events immunoregulation immunotoxicity improved insight novel novel marker performance tests prevent programmed cell death ligand 1 programmed cell death protein 1 randomized trial remote health care response risk stratification single-cell RNA sequencing success tertiary lymphoid organ tumor tumor-immune system interactions virtual working group

项目摘要

Immunotherapy has transformed the treatment landscape for a wide range of human malignancies. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block the immune regulatory “checkpoint” receptors, the Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4), Programmed Cell Death 1 (PD-1), or its ligand PD- L1. ICIs produce durable responses in many patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs), such as diabetic ketoacidosis (DKA) or thyroid disease, appearing to occur more frequently than originally expected. Immunotoxicity from cancer immunotherapy occurs in up to 90%, whereas autoimmune endocrine diseases occur in approximately 50% of patients treated with antibodies to CTLA-4 and/or PD-1/PD-L1. These irAEs can be serious or even life- threatening, such as autoimmune type 1 diabetes (T1D) presenting in DKA, and primary adrenal insufficiency caused by autoimmune adrenalitis. A recent study showed a marked increase of ICI-related autoimmune diabetes; reported in over 50% of the patients, with half of these patients presenting in DKA (50.2%). Thus, reliable biomarkers are needed to accurately stratify the risk of irAEs in patients who are candidates for these therapies (Aim I); these biomarkers may point to novel molecular pathways that could be targeted to prevent irAEs caused by immune checkpoint blockade (Aim II). Specifically, we will utilize the state-of-the-art single-cell platforms to investigate and characterize the comprehensive phenotypic and functional analyses of systemic cellular networks in patients with ICI-induced endocrinopathies. Our studies are greatly facilitated by the Baylor College of Medicine Immunotoxicity Working Group. Understanding the immunologic factors and the biomarkers associated with ICI-mediated inflammatory toxicities will be useful for the identification and early treatment of ICI-induced irAEs, and it may provide new insights into the pathoetiology and treatment of autoimmune endocrine diseases.

免疫疗法改变了多种人类恶性肿瘤的治疗格局。检查点抑制剂（ICIs）是阻断免疫调节“检查点”受体的单克隆抗体，细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4)、程序性细胞死亡 1 (PD-1) 或其配体 PD- L1. ICI 在许多患者中产生了持久的反应，然而，随着它们的成功，这些治疗方法也取得了成功。通常会引起多种免疫相关不良事件 (irAE)，例如糖尿病酮症酸中毒 (DKA) 或甲状腺疾病，似乎比最初预期的癌症免疫毒性发生得更频繁。免疫治疗的发生率高达 90%，而自身免疫内分泌疾病的发生率约为 50% 使用 CTLA-4 和/或 PD-1/PD-L1 抗体治疗的患者这些 irAE 可能是严重的，甚至是致命的。威胁，例如 DKA 中出现的自身免疫 1 型糖尿病 (T1D) 和原发性肾上腺皮质功能不全最近的一项研究表明，与 ICI 相关的自身免疫性肾上腺炎明显增加。超过 50% 的患者患有糖尿病；其中一半患者出现糖尿病酮症酸中毒 (50.2%)。需要可靠的生物标志物来准确分层适合这些患者的 irAE 风险疗法（目标 I）；这些生物标志物可能指向可用于预防的新分子途径具体来说，我们将利用最先进的单细胞来治疗由免疫检查点阻断引起的 irAE。研究和表征系统性基因的综合表型和功能分析的平台贝勒大学极大地促进了 ICI 引起的内分泌疾病患者的细胞网络。医学院免疫毒性工作组。了解免疫因素和生物标志物。与 ICI 介导的炎症毒性相关的研究将有助于识别和早期治疗 ICI 诱导的 irAE，可能为自身免疫内分泌的病理学和治疗提供新的见解疾病。