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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.

项目总结