权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Lab on a particle technology for functional screening of therapeutic cells

用于治疗细胞功能筛选的粒子技术实验室

基本信息

批准号：
10272940
负责人：
Dino Di Carlo
金额：
$ 26.32万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-09 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10272940
关键词：
Adhesives Adoption Affinity Alpha Particles Antibodies Antibody Formation Antigen Targeting Antigens Autologous Automobile Driving Bar Codes Biological Biological Assay Biomedical Engineering CD28 gene CD3 Antigens Caliber Capital Cell Adhesion Cell Survival Cell Therapy Cell surface Cell-Matrix Junction Cells Cellular biology Cellular immunotherapy Chemistry Chinese Hamster Ovary Cell Classification Clinical Clone Cells Custom Defense Mechanisms Development Diffuse Disease Encapsulated Engineering Ensure Enzyme-Linked Immunosorbent Assay Equipment Fluorescence Fluorescence-Activated Cell Sorting Generations Genetic Hematologic Neoplasms Hydrogels Immune Immunologics Immunotherapy Individual Interferon Type II Interferons Interleukin-2 Intervention Investments Knowledge Link Literature Lysine Malignant Neoplasms Measures Mediating Medicine Microfabrication Microfluidics Molecular Mus Outcome Ovalbumin Particle Size Patients Peptides Pharmaceutical Preparations Phenotype Population Procedures Process Production Property Proteins Recovery Relapse Reporting Research Research Personnel Signal Transduction Solid Neoplasm Sorting - Cell Movement Specificity Stains Standardization Structure Surface System T-Cell Receptor T-Lymphocyte T-cell diversity Techniques Technology Testing Therapeutic Time Transgenic Organisms Translating Tumor Immunity anti-cancer anticancer activity antigen-specific T cells base cancer cell cancer immunotherapeutics cancer therapy cell killing chimeric antigen receptor chimeric antigen receptor T cells cohort cost cytokine cytotoxicity design differential expression fluorescence activated cell sorter device gene therapy immunoengineering improved in vivo instrument instrumentation nanoDroplet nanosized new technology next generation novel particle patient subsets receptor response sample fixation screening success tool treatment optimization tumor

项目摘要

SUMMARY/ABSTRACT Engineered cell therapies have become a cornerstone of medicine, along with molecular (drugs and proteins) and genetic (gene therapy) interventions. However, new tools are needed to select, analyze, and design these “living drugs”. In the last few years, there has been particular success in the use of engineered immune cell- based therapies in treating hematologic malignancies, including recent FDA approvals of two chimeric antigen receptor (CAR)-T-cell products. Unfortunately, this success has not translated broadly, for example, to more prevalent solid tumors. One of the challenges in optimizing these therapies is that, unlike molecular therapies in which structure and function are intimately linked, cellular therapies are more difficult to functionally design, as conventional classifications of cells based on surface marker expression or target antigen affinity are poorly correlated with anti-cancer functions, such as cytokine secretion and cell killing. In fact, recent single-cell screens have highlighted an astonishingly high level of functional diversity from T-cells isolated from the same patient and bearing the same panel of surface markers, with only a small highly active subset of cells driving responses to immunological challenge. Various single-cell functional profiling platforms have emerged over the past several years, but their widespread adoption has been limited due to low assay throughputs, high-costs, or the need for skilled operators and expensive customized instrumentation. Broadly accessible technologies are needed to uncover the links between T-cell molecular and functional properties and anti-cancer activity, and ultimately, to enable the production and selection of the most efficacious cell therapies. We propose the development of a novel “lab on a particle” platform, which allows the rapid isolation of individual T-cells into uniformly sized nano-droplets, each formed by a microparticle with a structured cavity (termed a nanovial). This approach will provide simultaneous measures of both cell surface and secreted proteins, and recover cells with desired phenotypes at high rates using standard fluorescence-activated cell sorting (FACS) machines. Importantly, no knowledge of microfluidics or other specialized techniques is required to use nanovials. Our aims focus on: (1) developing nanovials with optimal adhesive properties for T-cell attachment and compatibility with a broad range of FACS instruments; and (2) sorting and characterizing individual antigen-specific T-cells based on interleukin-2 (IL-2) and interferon-γ (IFN-γ) production. We will test the hypothesis that T-cells sorted based on production of IL-2 and IFN-γ, as measured in nanovials, will have improved effector function. Our new technology promises to remove a significant barrier to entry in functional immune cell selection, and drive next-generation cancer immunotherapeutic design.

摘要/文摘