Sten Cell Gene Therapy of Breast Cancer

乳腺癌的 Sten 细胞基因治疗

基本信息

批准号：
7713333
负责人：
ANDRE Michael LIEBER
金额：
$ 32.37万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7713333
关键词：
Adverse effects Aniline Mustard Antibodies Apoptosis Beta-glucuronidase Biodistribution Birth Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone Marrow Transplantation Breast Cancer Model Breast Cancer Treatment Breast Carcinoma Cancer Control Cancer Patient Cell Count Cell Transplants Cells Collagen Cytostatics Cytotoxic agent Data Disease Dose Doxycycline Drug Controls Effector Cell Engraftment Fluorescent Dyes Gene Delivery Gene Expression Gene Expression Profile Gene-Modified Genes Genetic Glucuronides Goals Growth Factor Hematopoietic Neoplasms Hematopoietic stem cells Heterogeneity Home environment Homing Hormones Human Hypoxia Image Immune Immune Cell Activation Immune response Immunity Immunosuppressive Agents Improve Access In Vitro Inbred BALB C Mice Injection of therapeutic agent Intercellular Fluid Intravenous Investigational Therapies Laminin Lentivirus Vector Ligaments Liposomes Malignant Epithelial Cell Malignant Neoplasms Mediating Membrane Messenger RNA Methods MicroRNAs Modeling Molecular Profiling Mus Myelogenous Myeloid Cells Neoplasm Metastasis Nutrient Oncogenes Patients Pharmaceutical Preparations Population Preparation Procedures Prodrugs Proteins Publishing Rattus Recruitment Activity Relaxin Role Route Safety Series Source Staging Stem cell transplant Stem cells Stomas Subfamily lentivirinae Suicide Suspension substance Suspensions System T-Lymphocyte Testing Therapeutic Therapeutic Effect Tissues Transgenes Transgenic Mice Transplantation Treatment Efficacy Treatment Protocols Tumor-Derived Vaccination Variant Viral Virus antitumor agent base cancer cell cell stroma cell type chemotherapy clinically relevant cytokine density dosage extracellular gene therapy genetically modified cells in vivo irradiation killings lymph nodes macrophage malignant breast neoplasm mouse model nanoparticle neoplastic cell novel strategies peptide hormone pressure prevent progenitor promoter public health relevance reconstitution therapeutic transgene tool transgene expression tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Although tumor-specific immune cells are found in stage IV breast cancer patients, they are not able to control tumor growth. This is in part due to tumor stroma that tightly surrounds tumor nests. Tumor stroma contributes to immune evasion of breast cancer in at least two critical ways; by creating a physical barrier that prevents direct contact between tumor infiltrating immune cells and malignant cells, and by producing immunosuppressive cytokines that directly block activation of immune cells and/or attract/activate immuno-suppressive cells such as regulatory T-cells. In this proposal, we will test a new stem cell gene therapy approach that targets tumor stroma cells with the goal to enable existing immune cells to control tumor growth. The specific tumor microenvironment as well as cytokines/growth factors produced by tumor cells trigger differentiation of tumor-infiltrating hematopoietic tumor cells into a unique type of macrophages (so called tumor-associated macrophages -"TAMs"), with a gene expression signature that is distinct from that of tissue macrophages and myeloid cells. TAMs are the prevalent stroma cell type and the number of TAMs directly correlates with breast cancer malignancy. Our central hypotheses are that i) bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma, ii) the unique mRNA and microRNA expression profile of TAMs can be used to construct TAM-specific transgene expression systems, and iii) that drug controlled, transgene mediated killing of stroma cells and/or degradation of stroma protein enable long-term control of cancer. We provide a series of preliminary data that support the feasibility of our strategy. We will test our hypotheses in a mouse model of breast cancer involving rat neu-transgenic mice (neu-tg) and syngeneic mammary carcinoma cells (MMC). Key findings will be validated in a second breast cancer model that involves 4T1 cells and BALB/c mice. PUBLIC HEALTH RELEVANCE: Among the tumor stoma cells, tumor-associated macrophages (TAMs) are the prevalent cell type and the number of TAMs directly correlates with breast cancer malignancy. TAMs are a macrophage population that is phenotypically different from other tissue macrophages and bone marrow cells. Our central hypothesis is that bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma. Specifically, in a mouse model of breast cancer, we plan to genetically modify, ex vivo, bone marrow stem cells and transplant them into conditioned recipients where they engraft and provide a continuous source of TAM progenitor cells, thereby enabling long-term control of cancer. In this proposal we will focus on transgenes that eliminate obstacles to naturally existing anti-tumor immune cells, created by tumor stroma.

描述（申请人提供）：虽然在IV期乳腺癌患者中发现了肿瘤特异性免疫细胞，但它们无法控制肿瘤生长。这部分是由于肿瘤基质紧密包围肿瘤巢。肿瘤基质至少以两种关键方式促进乳腺癌的免疫逃避；通过创建物理屏障来防止肿瘤浸润免疫细胞和恶性细胞之间的直接接触，并通过产生直接阻止免疫细胞激活和/或吸引/激活免疫抑制细胞（例如调节性T细胞）的免疫抑制细胞因子。在这项提案中，我们将测试一种新的干细胞基因治疗方法，该方法针对肿瘤基质细胞，目标是使现有的免疫细胞能够控制肿瘤的生长。特定的肿瘤微环境以及肿瘤细胞产生的细胞因子/生长因子触发肿瘤浸润性造血肿瘤细胞分化为独特类型的巨噬细胞（所谓的肿瘤相关巨噬细胞-“TAM”），其基因表达特征为与组织巨噬细胞和骨髓细胞不同。 TAM 是常见的基质细胞类型，TAM 的数量与乳腺癌的恶性程度直接相关。我们的中心假设是：i) 骨髓来源的 TAM 祖细胞可用于将治疗性转基因传递至肿瘤基质，ii) TAM 独特的 mRNA 和 microRNA 表达谱可用于构建 TAM 特异性转基因表达系统，以及 iii)药物控制、转基因介导的基质细胞杀伤和/或基质蛋白降解能够长期控制癌症。我们提供了一系列初步数据来支持我们策略的可行性。我们将在涉及大鼠 neu 转基因小鼠 (neu-tg) 和同基因乳腺癌细胞 (MMC) 的乳腺癌小鼠模型中测试我们的假设。主要发现将在涉及 4T1 细胞和 BALB/c 小鼠的第二种乳腺癌模型中得到验证。公共卫生相关性：在肿瘤造口细胞中，肿瘤相关巨噬细胞 (TAM) 是常见的细胞类型，TAM 的数量与乳腺癌恶性程度直接相关。 TAM 是一个巨噬细胞群，其表型与其他组织巨噬细胞和骨髓细胞不同。我们的中心假设是，骨髓来源的 TAM 祖细胞可用于将治疗性转基因传递至肿瘤基质。具体来说，在乳腺癌小鼠模型中，我们计划对骨髓干细胞进行离体基因改造，并将其移植到条件接受者体内，在那里它们植入并提供持续的 TAM 祖细胞来源，从而实现癌症的长期控制。在这项提案中，我们将重点关注消除肿瘤基质产生的自然存在的抗肿瘤免疫细胞障碍的转基因。