In situ Imaging of CAR T-cells

CAR T 细胞的原位成像

基本信息

批准号：
8851136
负责人：
CHRISTINE BROWN
金额：
$ 22.19万
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 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851136
关键词：
Adoptive Immunotherapy Affect Affinity Animal Model Antibodies Antigen Targeting Antigens B lymphoid malignancy Binding Binding Sites CD28 gene Cell Culture Techniques Cetuximab Clinic Clinical Complex Cyclic Peptides Cytotoxic T-Lymphocytes Data Development Disease ERBB2 gene Engineering Epitopes Fab Immunoglobulins Foundations Gene-Modified Goals Half-Life Human 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 Staging Subfamily lentivirinae T cell therapy T-Lymphocyte Technology Tertiary Protein Structure Testing Therapeutic Therapeutic Monoclonal Antibodies Time Translating Transmembrane Domain Tumor Antigens antibody engineering antigen binding arm base cell killing cell transformation chemokine chimeric antigen receptor density extracellular imaging agent improved in vivo in vivo imaging innovation nanoparticle neoplastic cell next generation novel novel diagnostics public health relevance receptor response small molecule targeted imaging theranostics 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（由适用提供）：收养免疫疗法，该疗法利用使用一般重新设计的T细胞产生潜在的免疫响应，代表了一种治疗癌症和其他疾病的新型且强大的治疗方法。具体而言，对患者的T细胞进行了修饰，以表达嵌合抗原受体（CAR），该受体由肿瘤抗原识别结构域组成，该肿瘤抗原识别结构域与激活序列融合，在肿瘤抗原接合时会触发T细胞细胞毒性和增殖功能。该汽车的肿瘤抗原识别结构域通常是从单克隆抗体（MAB）中出现的单链可变片段（SCFV），以前选择以识别肿瘤抗原表位。在本文中，我们建议用碎片抗原结合结构域（FAB）或工程化以结合称为介体的环状肽的MAB代替SCFV结构域。将此媒介物结合位点掺入Fab/mab中，可独特地标记修饰的T细胞，并允许高度特异性，高亲和力与介体的相互作用，一种优化的，优化的血清稳定肽可以将包括DOTA，包括SCFV，趋化因子等或纳米颗粒在内的小分子共轭。因此，Incorporated Mediaiiatope界面提供了一个独特而及时的机会，可以快速，独立地为CAR T细胞疗法添加新功能。该应用程序的直接目标是证明具有媒介物的Fab或MAB可以有效地替换汽车内的SCFV，并可用于在体内对支持媒介物的汽车T细胞进行成像。这种新型相互作用的成功演示将为跟踪患者中支持介质的CAR T细胞奠定阶段，以将T细胞分布与临床结局相关联，并添加新的功能以改善这种新兴和广泛适用的疗法。