Most patients with neuroblastoma have widespread disease which is incurable by currently known methods. New therapeutic directions are needed. One novel approach is high dose chemotherapy and radiotherapy followed by autologous or allogeneic bone marrow transplantation. Such pilot studies are being carried out at Rainbow Babies and Childrens Hospital. We have developed five monoclonal antibodies (Mab) against human neuroblastoma (NB). Four of them are specific for ganglioside GD2 and one is specific for a neuro-ectodermal antigen NEA-1. These Mab have unique characteristics suitable for diagnostic and therapeutic applications. They include (1) the use of Mab to detect and remove NB cells in bone marrow before reinfusion, (2) the selective delivery of sterilizing doses of radiotherapy to NB in vivo. Such applications of Mab are particularly relevant for our autologous bone marrow transplantation program. We propose to define the tumor antigen heterogeneity in fresh NB specimens. By using a panel of Mab, we will attempt to overcome such heterogeneity in order to achieve 100% binding and tumor kill in the presence of Mab and complement. We will optimize complement dependent cytotoxicity of NB cells in the bone marrow to determine the most efficient and least toxic complement source. The binding and cytotoxicity of radiolabeled Mab to NB will be studied as the basis for in vivo Mab targeted radiotherapy. We will then attempt to treat human NB xenografted in nude mice using non-radiolabeled Mab alone and in the presence of complement. We will optimize the localization of radiolabeled Mab in NB as an imaging tool and as the groundwork for radiotherapy. By combining a panel of specific Mab in sequential treatments, we hope to achieve complete tumor sterilization with minimal normal tissue toxicity. Conjugates of Mab and metallic radionuclides will be used to further improve radiation delivery for better imaging and therapeutic results. It is likely that conclusions based on these studies will also be applicable to melanoma and osteogenic sarcoma. Our novel immunization schedule that has succeeded in producing these specific Mab may also be useful for other human cancers.
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