T LYMPHOCYTE RESPONSES TO HUMAN NEUROBLASTOMA

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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.