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.

免疫疗法已改变了各种人类恶性肿瘤的治疗局势。免疫检查点抑制剂（ICI）是单克隆抗体，可阻断免疫调节的“检查点”受体，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在许多患者中产生持久的反应。但是，再加上他们的成功，这些治疗方法通常会引起各种与免疫相关的广告事件（IRAE），例如糖尿病性酮症酸中毒（DKA）或甲状腺疾病，似乎比最初预期的更频繁。癌症免疫毒性免疫疗法最多发生90％，而自身免疫性内分泌疾病发生在大约50％用抗CTLA-4和/或PD-1/PD-L1治疗的患者。这些伊拉斯可能是严重的甚至是生命 - 威胁性，例如DKA中呈现的自身免疫性1型糖尿病（T1D）和初级肾上腺功能不全由自身免疫性肾上腺炎引起。最近的一项研究表明，与ICI相关的自身免疫显着增加糖尿病;报告了超过50％的患者，其中一半的患者出现在DKA中（50.2％）。那，需要可靠的生物标志物来准确地分层为这些候选者的伊拉斯的风险疗法（AIM I）；这些生物标志物可能指出可以针对的新分子途径由免疫检查点封锁引起的IRAE（AIM II）。具体来说，我们将利用最新的单细胞调查和表征全身性的全面表型和功能分析的平台 ICI诱导内分泌病患者的细胞网络。我们的研究由贝勒大量准备医学院免疫毒性工作组。了解免疫学因素和生物标志物与ICI介导的炎症毒性相关 ICI引起的IRAE，它可能会提供有关自身免疫性内分泌的病理学和治疗的新见解疾病。