CNS Anti-tumor immunity induced by dendritic cell vaccination and TLR agonists

树突状细胞疫苗和 TLR 激动剂诱导的 CNS 抗肿瘤免疫

• 批准号: 7754039
• 负责人: Robert M Prins
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754039
• 关键词: Agonist; Animal Model; Antigen-Presenting Cells; Autologous; Biodistribution; Brain Neoplasms; CD8B1 gene; Cell model; Central Nervous System Neoplasms; Clinical; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Epitopes; Glioma; Growth; Human; Image; Imiquimod; Immune response; Immune system; Immunity; Immunologics; Immunotherapy; In Vitro; Memory; Methodology; Mission; Modeling; Mus; Neoplasms; Neuraxis; Patients; Peptides; Peripheral; Physiologic pulse; Progress Review Group; Public Health; Research; Research Personnel; Sampling; T cell response; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic; Toll-like receptors; Transgenic Mice; Tumor Antigens; Tumor Immunity; Vaccination; base; cancer therapy; clinical efficacy; design; human TLR7 protein; in vivo; melanoma; melanoma-associated antigen; mouse model; pre-clinical; preclinical study; programs; stem; trafficking; tumor; tumor eradication

The broad, long-term objectives of our research are: i) to develop and optimize dendritic cell-based immunotherapy approaches for the treatment of brain tumors; and ii) to gain a better understanding of the mechanisms of immune responses generated by dendritic cell-based strategies targeting central nervous system (CMS) neoplasms. To do this, we propose three specific aims designed to understand, both in pre-clinical animal models as well as in clinical patient samples, the mechanisms of anti-tumor immunity critical for CMS tumor eradication. Immunotherapy for glioma has traditionally lagged behind other peripheral tumors where defined CTL targets are known. In our recent pre-clinical studies we have shown that both human and murine gliomas express melanoma-associated antigens (MAA)that can be recognized by the cellular immune system. We believe that the shared expression of MAA on gliomas and melanomas stems from their common neuroectodermal origin. Our discovery was important because it identified a set of endogenous tumor-associated antigens (TAA) on gliomas that have well characterized cytotoxic T lymphocyte (CTL) epitopes. Using our T cell receptor transgenic mouse model, in vivo imaging methodologies, and Toll-like receptor (TLR) agonists, we have designed a systematic set of studies to not only test the therapeutic value of targeting MAA on CMS tumors, but provide a model to test the basic immunological requirements for generating anti-tumor immunity to defined, endogenous MAA located in the CNS. Our central hypothesis is that CNS gliomas express MAA, which can be targeted by immunotherapies that enhance T cell and DC activation and trafficking. Thus, this is a mechanistic and translational project that is directly related to our long-term objectives stated above and to the mission of promoting public health.

我们研究的广泛，长期目标是：i）开发和优化基于树突的细胞 免疫疗法治疗脑肿瘤的方法； ii）更好地理解 针对中枢神经的基于树突细胞产生的免疫反应机制 系统（CMS）肿瘤。为此，我们提出了三个旨在理解的特定目标 临床前动物模型以及临床患者样品，抗肿瘤免疫的机制 对于消除CMS肿瘤至关重要。传统上，神经胶质瘤的免疫疗法落后于其他 已知明确的CTL靶标的周围肿瘤。在我们最近的临床前研究中，我们已经表明 人类和鼠神经胶质瘤都表达与黑色素瘤相关的抗原（MAA），可以是 被细胞免疫系统识别。我们相信MAA在神经胶质瘤上的共同表达 黑色素瘤源于它们常见的神经外皮起源。我们的发现很重要 因为它确定了一组内源性肿瘤相关的抗原（TAA） 特征性的细胞毒性T淋巴细胞（CTL）表位。使用我们的T细胞受体转基因小鼠模型， 体内成像方法和类似收费的受体（TLR）激动剂，我们设计了一个系统的集合 不仅要测试靶向MAA在CMS肿瘤上的治疗价值的研究，还为 测试为定义的内源性产生抗肿瘤免疫力的基本免疫学要求 MAA位于中枢神经系统中。我们的中心假设是CNS Gliomas Express MAA，这可以是 由增强T细胞和直流激活和运输的免疫疗法靶向。因此，这是一个 机械和翻译项目与我们上述长期目标直接相关， 促进公共卫生的使命。