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：
10019545
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/10019545
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 Drug resistance 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 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 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.

项目摘要嵌合抗原受体（CAR）T细胞代表了一种靶向抗药性癌症的令人兴奋的技术。这些细胞已被开发以有效靶向血液学恶性肿瘤，但是尚未发现对实体瘤的临床成功，这是癌症死亡率的大部分。实体瘤有无数的免疫抑制机制可防止有效的汽车T细胞疗法，新方法是需要阐明这些机制以及将这些单元的工程引向靶向实体瘤。该建议将采用一种综合的生物信息学方法来识别辅助目标在实体瘤或早期转移部位的部位增强CAR T细胞疗法。基质和免疫细胞将在这些部位的单细胞水平上进行测序，并与CAR T细胞疗法的功效进行比较。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蛋白质将在培养物中的CAR T细胞中动态成像，因为它们识别并靶向产生抗原细胞。这些不同数据集的计算集成将导致辅助目标将其内置到汽车设计。这些新结构将在体外和体内得到验证，并将为更先进的临床可用汽车T细胞疗法。