B cell-targeted CAR-T treatment of CNS Autoimmunity

B细胞靶向CAR-T治疗中枢神经系统自身免疫

基本信息

批准号：
10514950
负责人：
CHYI S HSIEH
金额：
$ 23.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10514950
关键词：
Adaptive Immune System Address Affinity Animal Model Antibodies Antigen Targeting Antigens Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B cell therapy B-Cell Antigen Receptor B-Lymphocytes Binding Biological Assay CAR T cell therapy CD4 Positive T Lymphocytes CNS Demyelinating Autoimmune Diseases CNS autoimmune disease CNS autoimmunity COVID-19 Cell Death Cell Survival Cell physiology Cells Central Nervous System Diseases Clinical/Radiologic Data Development Diagnostic Disease Epitopes Etiology Experimental Autoimmune Encephalomyelitis Exploratory/Developmental Grant Human Immunization Immunoglobulin G Immunosuppression Immunotherapy In Vitro Infection Inflammation Inflammatory Injury Knowledge Left Maintenance Mediating Methods Multiple Sclerosis Neuraxis Neurologic Neuromyelitis Optica Oligoclonal Bands Pathogenesis Pathogenicity Pathway interactions Patients Peptides Prevention Proteins Risk Role Safety Severities Signal Transduction Specificity Sum System T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Therapeutic Transgenic Organisms Treatment Efficacy Vaccines aquaporin 4 autoreactive B cell autoreactivity cell killing cell type central nervous system demyelinating disorder chimeric antigen receptor chimeric antigen receptor T cells exhaustion experience extracellular high reward high risk improved in vivo insight link protein mouse model neuroimmunologic disease neuroinflammation oligodendrocyte-myelin glycoprotein prevent response success targeted treatment

项目摘要

PROJECT SUMMARY An immense need for selective and antigen-specific immunotherapy without global immunosuppression exists for autoimmune diseases such as multiple sclerosis (MS). This has prompted exploration of chimeric antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. The contribution of B cells to MS and related diseases is recognized in part by the success of B cell depletion therapies. However, depletion of B cells for neuroimmunologic diseases are not selective enough to avoid safety concerns related to non-specific B cell depletion, including immunosuppression and infection. Hence, we seek to develop CAR T cells to target antigen-specific, autoreactive B cells using a B cell-dependent version of experimental autoimmune encephalomyelitis (EAE), an animal model with relevance to inflammatory demyelinating diseases of the central nervous system (CNS) such as MS. In preliminary studies, we have created a unique version of CAR T cells in which peptide MHCII (pMHCII) is fused with signaling domains in order to recognize specific T cell receptors (TCRs). We demonstrate that these pMHCII-CAR T cells specifically recognize a cognate TCR in vitro and in vivo and are capable of limiting EAE severity. We now seek to develop antigen-specific B cell depletion for the treatment of B cell-dependent EAE in two aims. In Aim 1, we will optimize survival of, and killing by, myelin oligodendrocyte glycoprotein (MOG)-expressing CAR T cells targeting MOG-specific B cells in both prevention and treatment of EAE. In Aim 2, we will utilize pMHCII-CAR T cells targeting MOG-specific TCRs in combination with MOG-CAR T cells targeting auto-reactive B cells in EAE. In sum, our proposed studies will explore the potential of a CAR T cell approach for the treatment of CNS autoimmunity by addressing how to optimally eliminate TCR and BCR specificities without leading to blanketed immunosuppression.

项目摘要不存在全局免疫抑制的选择性和抗原特异性免疫疗法的巨大需求用于自身免疫性疾病，例如多发性硬化症（MS）。这促使探索嵌合抗原受体（CAR）T细胞利用以特异性消除自动反应性细胞。 B细胞对MS的贡献与B细胞耗竭疗法的成功所识别的相关疾病得到了认可。但是，B耗尽神经免疫性疾病的细胞不足以避免与非特异性有关的安全问题 B细胞耗竭，包括免疫抑制和感染。因此，我们试图开发汽车T细胞以靶向抗原特异性的自动反应性B细胞使用B细胞依赖性的实验自身免疫性脑脊髓炎（EAE），一种与炎性脱髓鞘疾病相关的动物模型中枢神经系统（CNS），例如MS。在初步研究中，我们创建了一个独特的汽车版本肽MHCII（PMHCII）的细胞与信号域融合，以识别特定的T细胞受体（TCR）。我们证明了这些PMHCII-CAR T细胞特异性地识别了同源TCR 体外和体内，能够限制EAE的严重程度。我们现在寻求开发抗原特异性B细胞在两个目标中处理B细胞依赖性EAE的耗竭。在AIM 1中，我们将优化的生存和杀死，髓磷脂少突胶质细胞糖蛋白（MOG）表达靶向MOG特异性B细胞的CAR T细胞在预防和治疗EAE方面。在AIM 2中，我们将利用针对MOG特异性的PMHCII-CAR T细胞 TCR与靶向EAE自动反应性B细胞的MOG-CAR T细胞结合使用。总而言之研究将探讨CAR T细胞方法通过通过解决如何最佳地消除TCR和BCR特异性，而不会导致覆盖免疫抑制。