T LYMPHOCYTE RESPONSES TO HUMAN NEUROBLASTOMA

描述：（申请人的摘要）神经母细胞瘤是最常见的 儿童颅外实体瘤尝试开发一种有效的 神经母细胞瘤免疫治疗相对不成功。在 尽管这些失败，令人信服的临床证据表明，这些 肿瘤在某些情况下可以引发保护性免疫应答。 在其他癌症的有用免疫疗法方面取得了重大进展， 使用肿瘤特异性细胞毒性T淋巴细胞（CTL）来定义肿瘤 能够刺激治疗性免疫应答的抗原。 与在小鼠中容易产生神经母细胞瘤特异性CTL相反， 模型，几个小组已经报告了产生人类CTL的困难 对抗这个肿瘤PI最近成功地制造了肿瘤- 来自几个神经母细胞瘤患者的特异性CTL。在这个项目中，他 建议使用这些CTL来推进这种肿瘤的免疫治疗。的 该项目的具体目标是：1）使用这些CTL来测试 假设存在神经母细胞瘤肿瘤特异性抗原，以鉴定 这些抗原在分子水平上，并解释其表达 在肿瘤免疫学和生物学背景下的模式; 2）定义 体外产生CTL的最佳条件，以诱导这些T细胞 从目前耐药的肿瘤细胞，并延长有效性 过继性免疫疗法;以及3）为了检验定义的假设 神经母细胞瘤肿瘤抗原可以取代并超过天然肿瘤细胞， 产生抗肿瘤CTL应答。通过识别一个或多个 神经母细胞瘤肿瘤抗原和定义的最佳条件 产生抗肿瘤CTL反应，该项目将加速 为这种重要的儿科癌症开发免疫疗法。

DESCRIPTION: (Applicant's Abstract) Neuroblastoma is the most common extra-cranial solid tumor in children. Attempts to develop an effective immunotherapy for neuroblastoma have been relatively unsuccessful. In spite of these failures, compelling clinical evidence suggests that these tumors can elicit a protective immune response under some circumstances. Significant progress toward useful immunotherapy of other cancers has been made using tumor-specific cytotoxic T lymphocytes (CTL) to define tumor antigens which are capable of stimulating a therapeutic immune response. In contrast to the ease of generating neuroblastoma-specific CTL in murine models, several groups have reported difficulty producing human CTL against this neoplasm. The PI has recently succeeded in generating tumor- specific CTL from several neuroblastoma patients. In this project he proposes to use these CTL to advance immunotherapy of this neoplasm. The specific aims of this project are: 1) to use these CTL to test the hypothesis that neuroblastoma tumor-specific antigens exist, to identify these antigens at the molecular levels, and to interpret their expression patterns in the context of tumor immunology and biology; 2) to define the optimal conditions for CTL generation in vitro in order to elicit these T cells from currently resistant tumors and extend the effectiveness of adoptive immunotherapy; and 3) to test the hypothesis the defined neuroblastoma tumor antigens can replace and surpass native tumor cells in the generation of anti-tumor CTL responses. By identifying one or more neuroblastoma tumor antigens and defining the optimal conditions for generating an anti-tumor CTL response, this project will accelerate the development of immunotherapy for this important pediatric cancer.