Immune targeting of melanoma-associated antigens in glioma

描述（由申请人提供）：恶性胶质瘤是一类重要的中枢神经系统肿瘤，起源于神经胶质谱系。尽管传统的治疗方法最近取得了进展，但这些患者的预后并没有明显改变。在目前正在研究的治疗恶性癌症的新方法中，没有一种在理论上像免疫疗法那样吸引人，因为它提供了潜在的高肿瘤特异性毒性。中枢神经系统（CNS）胶质瘤的免疫治疗传统上落后于黑色素瘤等免疫原性肿瘤。可被免疫系统靶向的确定的胶质瘤相关抗原（GAA）的相对缺乏可能部分解释了这种情况。在人类和小鼠临床前模型中，存在于黑色素瘤上的抗原已被广泛表征。黑素细胞和星形胶质细胞在胚胎学上都来源于神经外胚层。它们的肿瘤对应物，恶性黑色素瘤和胶质瘤，已经在人类中被证明在RNA水平上具有共同的抗原。然而，关于神经胶质瘤是否可以通过免疫策略靶向，即将T细胞诱导到黑色素瘤相关抗原（MAA）的表位，我们知之甚少。本提案中概述的实验主要旨在测试MAA是否在胶质瘤中表达并被免疫系统识别。该提案还将确定靶向位于中枢神经系统内的肿瘤的基本免疫学要求。本研究结果不仅为中枢神经系统中T淋巴细胞应答提供了重要的基础免疫学数据，而且可能为中枢神经系统肿瘤的临床治疗提供新的免疫治疗靶点。加州大学洛杉矶分校的肿瘤免疫学项目和学术环境为独立研究科学家的发展提供了理想的场所。许多学科的世界知名科学家和技术将有助于提高普林斯博士的能力，以实现本申请中提出的目标。

DESCRIPTION (provided by applicant): Malignant gliomas represent a significant class of CNS tumors derived from the glial lineage. Despite recent advances in traditional treatment options, the prognosis for these patients has not changed appreciably. Among the new treatments currently being investigated for malignant cancers, none is as theoretically appealing as immunotherapy because it offers the potential for high tumor-specific toxicity. Immune-based treatments for central nervous system (CNS) gliomas have traditionally lagged behind those of more immunogenic tumors such as melanoma. The relative paucity of defined glioma-associated antigens (GAA) that can be targeted by the immune system may partially account for this situation. Antigens present on melanomas have been extensively characterized, both in humans and murine pre-clinical models. Melanocytes and astrocytes are both derived embryologically from the neural ectoderm. Their neoplastic counterparts, malignant melanomas and gliomas, have been shown in humans to share common antigens at the RNA level. However, little is known concerning whether gliomas can be targeted by immune-based strategics that prime T cells to epitopes from melanoma-associated antigens (MAA). The experiments outlined in this proposal are primarily designed to test whether MAA are expressed by gliomas and recognized by the immune system. This proposal will also define the basic immunologic requirements for targeting tumors located within the CNS. The results from this study should not only provide important basic immunologic data concerning T lymphocyte responses in the CNS, but could potentially outline a new immunotherapeutic target for CNS tumors clinically. The tumor immunology program and academic environment at UCLA offers an ideal place to develop as an independent research scientist. World renowned scientists and technology in many disciplines will serve to enhance the ability of Dr. Prins to accomplish the goals set forth in this application.