Chimeric Antigen Receptor T Cell Design Through Living Cell Systems Biology

通过活细胞系统生物学进行嵌合抗原受体 T 细胞设计

基本信息

批准号：
10457370
负责人：
Joseph Thomas Decker
金额：
$ 12.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457370
关键词：
Adjuvant Adjuvant Therapy Adoptive Transfer Antibodies Antigen Targeting Archives Bioinformatics Cells Cellular immunotherapy Cessation of life Clinical Clinical Treatment Coculture Techniques Complex Cytotoxic T-Lymphocytes Data Data Set Disease Disseminated Malignant Neoplasm Drug Targeting ERBB2 gene Elements Emerging Technologies Engineering Environment Exhibits Fellowship Foundations Genes Genetic Transcription Goals Hematologic Neoplasms Heterogeneity Human Image Immune Immunologic Surveillance In Vitro Individual Integrins Lead Location Lymphocyte Malignant Neoplasms Mediating Methods Modeling Mouse Strains Pathway interactions Patients Phenotype Population Positioning Attribute Proliferating Property Proteins Reporter Research Activity Resistance Route Sampling Series Signal Transduction Signaling Molecule Site Solid Solid Neoplasm Stromal Cells System Systems Biology T cell therapy T-Lymphocyte Technology Therapeutic Time Tissue Engineering To specify Training Trastuzumab Validation antigen-specific T cells base cell type cellular imaging chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical application cofactor cytotoxic cytotoxicity data-driven model design engineered T cells experimental study immune resistance immunoengineering improved in vivo insight interest live cell imaging live cell microscopy malignant breast neoplasm mortality neoplastic cell paracrine prevent refractory cancer screening single cell sequencing single-cell RNA sequencing success synthetic biology transcription factor tumor tumor-immune system interactions

项目摘要

Project Summary Chimeric antigen receptor (CAR) T cells represent an exciting technology for targeting drug-resistant cancers. These cells have been developed to effectively target hematological malignancies, however have yet to find clinical success against solid tumors, which account for the majority of cancer mortality. Solid tumors have myriad immunosuppressive mechanisms that prevent effective CAR T cell therapies, and new methods are needed to both elucidate these mechanisms as well as direct the engineering of these cells towards targeting solid tumors. This proposal will take an integrated bioinformatic approach to identifying adjuvant targets to enhance CAR T cell therapy at the site of a solid tumor or early metastatic site. Stromal and immune cells will be sequenced at the single cell level at these sites and compared to efficacy of CAR T cell therapy. These sequencing results will guide live cell imaging experiments, in which key transcription factors and effector proteins will be dynamically imaged in CAR T cells in culture as they recognize and target antigen-producing cells. Computational integration of these disparate datasets will result in adjuvant targets that will be built into the CAR design. These new constructs will be validated both in vitro and in vivo and will provide the basis for more advanced clinically available CAR T cell therapies.

项目概要嵌合抗原受体 (CAR) T 细胞代表了一项令人兴奋的针对耐药癌症的技术。这些细胞已被开发用于有效靶向血液恶性肿瘤，但尚未发现实体瘤的临床成功，实体瘤占癌症死亡率的大部分。实体瘤有多种免疫抑制机制阻碍了有效的 CAR T 细胞疗法，而新方法正在出现需要阐明这些机制以及指导这些细胞的工程靶向实体瘤。该提案将采用综合生物信息学方法来确定辅助靶标增强实体瘤部位或早期转移部位的 CAR T 细胞治疗。基质细胞和免疫细胞将在这些位点的单细胞水平上进行测序，并与 CAR T 细胞疗法的疗效进行比较。这些测序结果将指导活细胞成像实验，其中关键转录因子和效应子当蛋白质识别并靶向产生抗原时，将在培养的 CAR T 细胞中对蛋白质进行动态成像细胞。这些不同数据集的计算集成将产生辅助目标，这些目标将内置于汽车设计。这些新的构建体将在体外和体内得到验证，并将为更先进的临床可用 CAR T 细胞疗法。