CAR-T cell treatment of CNS Autoimmunity

CAR-T细胞治疗中枢神经系统自身免疫

基本信息

批准号：
10641913
负责人：
CHYI S HSIEH
金额：
$ 68.34万
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：
2022-06-13 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641913
关键词：
Address Affinity Algorithms Animal Model Antibodies Antigen Presentation Antigen Receptors Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Binding CAR T cell therapy CASP3 gene CASP8 gene CD28 gene CD3 Antigens CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CNS Demyelinating Autoimmune Diseases CNS autoimmune disease CNS autoimmunity CRISPR/Cas technology Cell Death Induction Cells Central Nervous System Diseases Chronic Clinical Data Disease Dominant-Negative Mutation Engineering Epitopes Excision Experimental Autoimmune Encephalomyelitis Frequencies Gene Deletion Gene Targeting Genes Goals Granzyme HLA-DR Antigens Healthcare Human Immune response Immune system Immunosuppression Immunotherapy In Vitro Inflammation JUN gene Knock-out Libraries Lymphocyte Methodology Modeling Modification Multiple Sclerosis Mus Myelin Proteins Nervous System Trauma Pathogenesis Pathway interactions Patients Peptide Receptor Peptides Prevention Proteins Reaction Resolution Severities Signal Transduction Specificity T-Cell Antigen Receptor Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes T-cell receptor repertoire Technology Testing Transgenic Organisms Translating Tumor Necrosis Factor-Beta Validation adaptive immunity autoreactive T cell autoreactivity cancer therapy care burden cell killing chemical reaction chimeric antigen receptor chimeric antigen receptor T cells disability efficacy evaluation exhaustion experimental study feasibility testing genetic linkage human disease improved in vivo in vivo evaluation mouse model multiple sclerosis treatment neuroinflammation oligodendrocyte-myelin glycoprotein optimal treatments overexpression perforin pre-clinical receptor response translation to humans vector

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) and a closely related condition known as myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). This has prompted exploration of chimeric antigen receptor (CAR) T cell utilization to specifically eliminate autoreactive cells. We have created a unique version of CAR T cells in which peptide MHCII (pMHCII) was fused with signaling domains in order to recognize specific T cell receptors (TCRs). In preliminary studies we demonstrate that these pMHCII-CAR T cells specifically recognize a cognate TCR in vitro and can selectively kill antigen-specific CD4 T cells in vivo. Efficient depletion of high affinity MOG-specific CD4 T cells was associated with prevention of MOG-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Modifications in pMHCII-CAR construction led to greater efficiency in eliminating lower-affinity MOG-reactive T cells which was associated with resolution of ongoing EAE. These data suggest an “activation energy” model of autoimmunity analogous to that of a chemical reaction, in which higher affinity self-reactive T cells are needed to provide the activation energy to initiate autoimmunity, but lower affinity T cells are capable of sustaining the autoimmune “reaction.” To address the hypothesis that CAR T cell technology can be used to eliminate auto-antigen-specific T cells and abrogate central nervous system (CNS) autoimmunity in mice and humans without global immunosuppression, we have formulated three specific aims. In Aim 1 we will improve the efficiency of low affinity T cell deletion in vivo. In Aim 2, we will test whether we can successfully target autoreactive CD4 T cells specific to all T cell epitopes of a protein in mice, as we predict that such an approach would be useful for treatment of human disease where the T cell autoantigen is identified by an autoantibody. Finally, in Aim 3, we will directly test whether MOGAD patients show an increased frequency of MOG-specific T cells using pMHCII-CARs for antigen discovery. In sum, our proposed studies will explore the “activation energy” model of autoimmunity and establish an optimal CAR T cell approach to eliminate low affinity autoreactive TCR specificities for the treatment of ongoing autoimmune disease. Finally, we will begin to translate these murine observations to human pMHCII-CAR T cells and assess their potential utility in a relevant human autoimmune CNS disease.

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治疗自身免疫性疾病，例如多发性硬化症 (MS) 和一种密切相关的髓鞘质疾病少突胶质细胞糖蛋白（MOG）抗体疾病（MOGAD）这促使人们探索嵌合体。利用抗原受体 (CAR) T 细胞特异性消除自身反应性细胞。 CAR T 细胞版本，其中肽 MHCII (pMHCII) 与信号结构域融合以识别在初步研究中，我们证明这些 pMHCII-CAR T 细胞。体外特异性识别同源 TCR，并能在体内选择性杀伤抗原特异性 CD4 T 细胞。高亲和力 MOG 特异性 CD4 T 细胞的耗竭与预防 MOG 诱导的实验自身免疫性脑脊髓炎（EAE），一种 MS 动物模型，pMHCII-CAR 构建的修改导致了这种情况。消除低亲和力 MOG 反应性 T 细胞的效率更高，这与分辨率相关这些数据表明自身免疫的“活化能”模型类似于化学物质的模型。反应，其中需要更高亲和力的自反应 T 细胞来提供启动能量自身免疫，但亲和力较低的 T 细胞能够维持自身免疫“反应”。假设 CAR T 细胞技术可用于消除自身抗原特异性 T 细胞并消除中枢神经系统在没有整体免疫抑制的情况下，我们发现小鼠和人类的神经系统（CNS）自身免疫在目标 1 中，我们将提高体内低亲和力 T 细胞删除的效率。 2，我们将测试是否可以成功靶向特定于某个特定 T 细胞表位的自身反应性 CD4 T 细胞小鼠体内的蛋白质，正如我们预测的那样，这种方法将有助于治疗人类疾病，其中最后，在目标 3 中，我们将直接检测是否为 MOGAD 患者。显示使用 pMHCII-CAR 进行抗原发现的 MOG 特异性 T 细胞的频率增加。拟议的研究将探索自身免疫的“活化能”模型并建立最佳的CAR T细胞消除低亲和力自身反应性 TCR 特异性的方法，用于治疗正在进行的自身免疫性疾病。最后，我们将开始将这些小鼠观察结果转化为人类 pMHCII-CAR T 细胞并评估其在相关人类自身免疫性中枢神经系统疾病中的潜在用途。