Immune targeting of melanoma-associated antigens in glioma

描述（由申请方提供）：恶性神经胶质瘤是一类重要的神经胶质细胞系CNS肿瘤。尽管传统的治疗方法取得了最新进展，但这些患者的预后并没有明显改变。在目前正在研究的恶性肿瘤新疗法中，没有一种疗法在理论上像免疫疗法那样有吸引力，因为它提供了高肿瘤特异性毒性的潜力。中枢神经系统（CNS）胶质瘤的免疫治疗传统上落后于免疫原性更强的肿瘤，如黑色素瘤。可被免疫系统靶向的确定的神经胶质瘤相关抗原（GAA）的相对缺乏可能部分地解释了这种情况。在人和鼠临床前模型中，黑素瘤上存在的抗原已被广泛表征。黑素细胞和星形胶质细胞都是从胚胎学上来源于神经外胚层。它们的肿瘤对应物，恶性黑色素瘤和神经胶质瘤，已经显示在人类中在RNA水平上共享共同抗原。然而，关于胶质瘤是否可以通过基于免疫的策略来靶向，该策略将T细胞引导至来自黑素瘤相关抗原（MAA）的表位，知之甚少。本提案中概述的实验主要旨在测试MAA是否由神经胶质瘤表达并被免疫系统识别。该提案还将定义靶向CNS内肿瘤的基本免疫学要求。本研究的结果不仅为CNS T淋巴细胞反应提供了重要的基础免疫学数据，而且可能为临床CNS肿瘤的免疫治疗提供新的靶点。UCLA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。世界知名的科学家和许多学科的技术将有助于提高普林斯博士完成本申请中提出的目标的能力。

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.