Immune targeting of melanoma-associated antigens in glioma

描述(申请人提供)：恶性胶质瘤是一类重要的中枢神经系统肿瘤，起源于神经胶质细胞谱系。尽管最近在传统治疗方案上取得了进展，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肿瘤的新疗法中，没有一种疗法在理论上像免疫疗法那样吸引人，因为它具有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黑色素瘤等免疫原性更强的肿瘤。免疫系统可靶向的明确的胶质瘤相关抗原(GAA)的相对缺乏可能是造成这种情况的部分原因。黑色素瘤上存在的抗原在人类和小鼠的临床前模型中都有广泛的特征。黑素细胞和星形胶质细胞都是神经外胚层的胚胎学来源。他们的肿瘤对应物，恶性黑色素瘤和胶质瘤，已经被证明在人类身上在RNA水平上共享共同的抗原。然而，关于胶质瘤是否可以通过基于免疫的策略来针对黑色素瘤相关抗原(MAA)的表位而启动T细胞，人们知之甚少。这项提案中概述的实验主要是为了测试MAA是否在胶质瘤中表达并被免疫系统识别。该提案还将定义针对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，而且可能为临床治疗中枢神经系统肿瘤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课程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Prins博士实现本申请中设定的目标的能力。

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.