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

描述(申请人提供)：我们研究的广泛和长期目标是：i)开发和优化基于树突状细胞的免疫治疗方法用于脑肿瘤的治疗；以及ii)更好地了解针对中枢神经系统(CMS)肿瘤的基于树突状细胞的策略产生免疫反应的机制。为了做到这一点，我们提出了三个特定的目标，旨在了解在临床前动物模型和临床患者样本中，抗肿瘤免疫对CMS肿瘤根除至关重要的机制。胶质瘤的免疫治疗传统上落后于其他已知CTL靶点的外周肿瘤。在我们最近的临床前研究中，我们已经证明人类和小鼠胶质瘤都表达黑色素瘤相关抗原(MAA)，这种抗原可以被细胞免疫系统识别。我们认为MAA在胶质瘤和黑色素瘤中的共同表达源于它们共同的神经外胚层起源。我们的发现很重要，因为它确定了一组胶质瘤的内源性肿瘤相关抗原(TAA)，这些抗原具有良好的细胞毒性T淋巴细胞(CTL)表位特征。利用我们的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，我们设计了一套系统的研究，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，测试针对位于中枢神经系统的明确的内源性MAA产生抗肿瘤免疫的基本免疫学要求。我们的中心假设是，中枢神经系统胶质瘤表达MAA，它可以作为免疫疗法的靶点，增强T细胞和DC的激活和运输。因此，这是一个机械性和转化性的项目，与我们上文所述的长期目标和促进公共卫生的使命直接相关。

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.