Generation of therapeutic T cells from cord blood-derived stem cells

从脐带血干细胞生成治疗性 T 细胞

基本信息

批准号：
7633360
负责人：
KRISHNENDU ROY
金额：
$ 22.13万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-05 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633360
关键词：
Adoptive Transfer Antigen-Presenting Cells Antigens Autologous Binding Bone Marrow CD8 Antigens CD8B1 gene Cell Differentiation process Cell Lineage Cell Separation Cell Therapy Cells Commit Controlled Environment Disease Doctor of Philosophy Engineering Gene Expression Generations Genes Goals Hematopoietic stem cells Human Immunotherapy In Vitro Ligands Magnetism Malignant Neoplasms Marrow Methods Microspheres Molecular Morbidity - disease rate Multipotent Stem Cells Mus Notch Signaling Pathway Paracrine Communication Pathway interactions Patient Education Patients Population Principal Investigator Production Proto-Oncogene Protein c-kit Reporting Research Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Source Staging Stem cells Stromal Cells Surface System T-Cell Development T-Lymphocyte Technology Therapeutic Thymus Gland Time Training Transplantation Umbilical Cord Blood base high throughput technology notch protein particle peripheral blood programs public health relevance technology development

项目摘要

DESCRIPTION (provided by applicant): In recent years, successful ex-vivo immunotherapy with autologous T cells (adoptive transfer) has been reported for a variety of cancers. However, current efforts to provide therapeutic T cells for such therapy involve isolation of cells from the patient's peripheral blood, expansion and antigen specific "training" ex-vivo followed by return of the trained cells into the patient. These methods are severely constrained by (a) the difficulties and inefficiency of patient cell isolation (b) problems with expansion of primary cells in vitro (c) the morbidity associated with autologous cell therapy and above all (d) the limited availability of donor cells. In addition, the time required to "expand" and "train" patient-isolated cells for adoptive therapy can often prove to be too long for critical diseases. Therefore, technologies leading to efficient generation and expansion of therapeutic T cells from multipotent stem cells in a synthetic, controlled environment could provide a renewable, on-demand and readily available cell source for a variety of disease applications. Despite tremendous advances in the past few years in our understanding of the molecular signals involved in T cell development, the ultimate therapeutic applicability of stem cell-derived T cells require (a) Quantitative understanding of microenvironment- directed hematopoietic progenitor cell (HPC) differentiation into T cells and (b) Development of technologies for high-throughput production of functional, antigen- specific T cells suitable for on-demand transplantation. Our goal here is to engineer artificial T cell development niches (synthetic thymus-like microenvironment) to understand the effects of controlled Notch signaling in T cell development and direct human HPCs into therapeutic T cells in a scalable manner. Specifically, we propose to synthesize notch-ligand functionalized (artificial thymic stromal cells) and HLA tetramer functionalized magnetic microbeads (artificial antigen presenting cells), and evaluate how cord blood-derived human CD34+CD38- stem cells could be directed to functional, therapeutic T cells. PUBLIC HEALTH RELEVANCE: The goal of this two year project is to develop synthetic microbeads that mimic the micro-environmental conditions of the thymus in order to study how cord blood- derived hematopoietic progenitor cells can be directed to the T cell lineage. Specifically we would investigate how efficient notch signaling through these artificial stromal cells could trigger notch specific genes and in the presence of paracrine signals from mouse or human stromal cell signals generate early T cells. We would also investigate if tetramer signaling through magnetic microbeads (artificial antigen presenting cells) can further differentiate these stem cell-derived early T cells into more mature, CD8+ antigen specific T cells.

描述（由申请人提供）：近年来，已经报道了各种癌症的自体T细胞（收养转移）成功的外部免疫疗法（收养转移）。但是，目前为这种治疗提供治疗性T细胞的努力涉及从患者的外周血，膨胀和特定于抗原特异性“训练”的Ex-Vivo分离细胞，然后将训练有素的细胞返回患者。这些方法受（a）患者细胞分离的困难和效率低下（b）体外膨胀的困难和效率低下（c）与自体细胞疗法相关的发病率，尤其是（d）供体细胞的有限利用率有限。此外，“扩展”和“训练”患者分散疗法所需的时间通常可能被证明是严重疾病的时间太长。因此，在合成，受控的环境中，从多能干细胞中有效产生和扩展从多能干细胞的技术产生和扩展的技术可以为多种疾病应用提供可再生，点播和随时可用的细胞来源。尽管在过去的几年中，我们对参与T细胞开发的分子信号的理解取得了巨大进步，但干细胞衍生的T细胞的最终治疗适用性需要（a）对微环境的定量理解微环境定向的造血祖细胞（HPC）分化为T细胞和（b）开发用于高通量产生功能性抗原特异性T细胞的技术。我们的目标是设计人造T细胞发育thees（合成胸腺样微环境），以了解受控Notch信号在T细胞发育中的影响，并以可扩展的方式将人类HPC引入治疗性T细胞。 Specifically, we propose to synthesize notch-ligand functionalized (artificial thymic stromal cells) and HLA tetramer functionalized magnetic microbeads (artificial antigen presenting cells), and evaluate how cord blood-derived human CD34+CD38- stem cells could be directed to functional, therapeutic T细胞。公共卫生相关性：这两年项目的目标是开发模仿胸腺的微环境条件的合成微粒，以研究如何将脐带血造成的造血祖细胞定向到T细胞谱系。具体而言，我们将研究如何通过这些人造的人造细胞通过小鼠或人类基质细胞信号的旁分泌信号引发缺口基因的有效凹口信号传导产生早期T细胞。我们还将研究通过磁性微粒（人造抗原呈递细胞）的四聚体信号传导是否可以进一步将这些干细胞衍生的早期T细胞分为更成熟的CD8+抗原特异性T细胞。