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

描述（由申请人提供）：我们研究的广泛、长期目标是：i）开发和优化用于治疗脑肿瘤的基于树突状细胞的免疫治疗方法; ii）更好地了解靶向中枢神经系统（CMS）肿瘤的基于树突状细胞的策略产生的免疫应答机制。为了做到这一点，我们提出了三个具体的目标，旨在了解，无论是在临床前的动物模型，以及在临床患者样本，抗肿瘤免疫的机制CMS肿瘤根除的关键。神经胶质瘤的免疫治疗传统上落后于其他外周肿瘤，其中确定的CTL靶点是已知的。在我们最近的临床前研究中，我们已经表明人和鼠胶质瘤都表达可以被细胞免疫系统识别的黑素瘤相关抗原（MAA）。我们认为，共同表达的MAA神经胶质瘤和黑色素瘤源于他们共同的神经外胚层起源。我们的发现是重要的，因为它确定了一组内源性肿瘤相关抗原（TAA）的神经胶质瘤，具有良好的特点细胞毒性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Toll样受体（TLR）激动剂，我们设计了一组系统的研究，不仅测试靶向MAA对CMS肿瘤的治疗价值，而且提供了一个模型来测试对位于CNS中的确定的内源性MAA产生抗肿瘤免疫的基本免疫学要求。我们的中心假设是CNS胶质瘤表达MAA，其可以被增强T细胞和DC活化和运输的免疫疗法靶向。因此，这是一个与我们上述长期目标和促进公共卫生的使命直接相关的机械和转化项目。

DESCRIPTION (provided by applicant): 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.