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In situ Imaging of CAR T-cells

CAR T 细胞的原位成像

基本信息

批准号：
9274922
负责人：
CHRISTINE BROWN
金额：
$ 25.88万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274922
关键词：
Adoptive Immunotherapy Affinity Animal Model Antibodies Antigen Targeting Antigens Armadillo Repeat B lymphoid malignancy Binding Binding Sites Biochemical CD28 gene Cell Culture Techniques Cell Therapy Cetuximab Clinic Clinical Complex Cyclic Peptides Cytotoxic T-Lymphocytes Data Development Disease ERBB2 gene Engineering Epitopes Fab Immunoglobulins Foundations Gene-Modified Goals Half-Life Image Immune response Immunotherapy In Situ In Vitro Label Malignant Neoplasms Monoclonal Antibodies Mus Names Outcome Patients Peptides Positron-Emission Tomography Protein Binding Domain Proteins Research Safety Serum Signal Transduction Site T-Lymphocyte Technology Tertiary Protein Structure Testing Therapeutic Therapeutic Monoclonal Antibodies Time Translating Transmembrane Domain Tumor Antigens antibody engineering antigen binding base cell killing cell transformation chemokine chimeric antigen receptor density extracellular human monoclonal antibodies imaging agent improved improved functioning in situ imaging in vivo in vivo imaging innovation lentivirally transduced nanoparticle neoplastic cell next generation novel novel diagnostics public health relevance receptor response small molecule targeted imaging theranostics therapy outcome trafficking tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): Adoptive immunotherapy, which capitalizes on generating a potent immune response using genetically re- engineered T cells, represents a novel and powerful therapeutic approach to treat cancer and other diseases. Specifically, patient's T cells are modified to express a chimeric antigen receptor (CAR), which consists of a tumor antigen recognition domain fused to an activation sequence that triggers T cell cytotoxic and proliferative functions when tumor antigen is engaged. The tumor antigen recognition domain of the CAR is commonly a single chain variable fragment (scFv) excised from a monoclonal antibody (mAb) previously selected to recognize a tumor antigen epitope. Herein, we propose to replace the scFv domain with either a fragment antigen-binding domain (Fab) or a mAb that are engineered to bind a cyclic peptide called meditope. Incorporation of this meditope-binding site within the Fab/mAb uniquely marks the modified T cells and permits a highly specific, high affinity interaction with a meditope, an optimized, serum stable peptide that can be conjugated to small molecules including DOTA, biologics including scFvs, chemokines, etc., or nanoparticles. As such, the incorporation of the meditope interface offers the unique and timely opportunity to rapidly and independently add new functionality to CAR T cell therapy. The immediate goal of this application is to demonstrate that a meditope-enabled Fab or mAb can effectively replace the scFv within the CAR and can be used to image meditope-enabled CAR T cells in vivo. Successful demonstration of this novel interaction will set the stage to track meditope-enabled CAR T cells in patients, to correlate T cell distributions with clinical outcomes, and to add new functionality to improve this emerging and broadly applicable therapy.

描述(申请人提供)：过继免疫疗法，它利用基因重新工程的T细胞产生强大的免疫反应，代表了一种治疗癌症和其他疾病的新的和强大的治疗方法。具体地说，患者的T细胞被修饰为表达嵌合抗原受体(CAR)，该受体由肿瘤抗原识别结构域与激活序列融合组成，当肿瘤抗原被结合时，激活序列触发T细胞的细胞毒和增殖功能。CAR的肿瘤抗原识别结构域通常是从先前为识别肿瘤抗原表位而选择的单抗(MAb)中切下的单链可变区(ScFv)。在这里，我们建议用片段抗原结合域(Fab)或mAb来取代scFv结构域，这些结构域被设计成与一种名为Meditope的环肽结合。在Fab/mAb中加入这个表位结合位点可以唯一地标记修饰的T细胞，并允许与表位高度特异、高亲和力的相互作用，表位是一种优化的、血清稳定的多肽，可与DOTA等小分子、单链抗体、趋化因子等生物制品或纳米粒结合。因此，Meditope界面的加入为CAR T细胞治疗提供了快速和独立地添加新功能的独特和及时的机会。这项应用的直接目标是证明冥想启用的Fab或mAb可以有效地取代汽车内的scFv，并可用于体内成像启用冥想的CAR T细胞。这种新的相互作用的成功展示将为追踪患者体内启用冥想的CAR T细胞，将T细胞分布与临床结果相关联奠定基础，并增加新的功能，以改进这一新兴和广泛适用的疗法。