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：
10677698
负责人：
CHYI S HSIEH
金额：
$ 19.44万
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/10677698
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 pandemic Cell Death Induction Cell Survival Cell physiology Cells Central Nervous System 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 Neurologic Neuromyelitis Optica Oligoclonal Bands Pathogenesis Pathogenicity Pathway interactions Patients Peptides Prevention Proteins Risk Role Safety Severities Signal Transduction Specificity 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 disability efficacy evaluation 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.

项目概要存在对无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）。这促使人们探索嵌合抗原利用受体 (CAR) T 细胞特异性消除自身反应性细胞。 B 细胞对 MS 的贡献 B 细胞耗竭疗法的成功在一定程度上认识到了疾病和相关疾病的存在。然而，B 的耗尽神经免疫疾病细胞的选择性不够，无法避免与非特异性相关的安全问题 B 细胞耗竭，包括免疫抑制和感染。因此，我们寻求开发 CAR T 细胞来靶向使用实验性自身免疫的 B 细胞依赖性版本的抗原特异性、自身反应性 B 细胞脑脊髓炎（EAE），一种与炎症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，我们创建了独特版本的 CAR T 肽 MHCII (pMHCII) 与信号结构域融合以识别特定 T 细胞的细胞受体（TCR）。我们证明这些 pMHCII-CAR T 细胞特异性识别同源 TCR 体外和体内，并且能够限制 EAE 的严重程度。我们现在寻求开发抗原特异性 B 细胞耗竭治疗 B 细胞依赖性 EAE 有两个目的。在目标 1 中，我们将优化生存，并且表达髓磷脂少突胶质细胞糖蛋白 (MOG) 的 CAR T 细胞针对 MOG 特异性 B 细胞进行杀伤预防和治疗EAE。在目标 2 中，我们将利用针对 MOG 特异性的 pMHCII-CAR T 细胞 TCR 与 MOG-CAR T 细胞结合，靶向 EAE 中的自身反应性 B 细胞。总而言之，我们提出的研究将探索 CAR T 细胞方法治疗中枢神经系统自身免疫的潜力解决如何以最佳方式消除 TCR 和 BCR 特异性而不导致覆盖免疫抑制。