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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：
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.