427. Adenovirus Mediated GRP94/gp96 Expression in Treatment of Neuroblastoma

Abstract

Top of pageAbstract Neuroblastoma is one of the most common solid tumors of childhood. Response to conventional therapy in patients with advanced stage disease is low and mortality is high. Novel therapeutic approaches that improve patient survival are clearly needed. Tumor- derived glucose-regulated protein 94 (GRP94/gp96), a HSP90 family member, has shown great promise as a tumor vaccine. In this study, we explored the therapeutic efficacy of a combined GRP94/gp96- based genetic immunotherapy and radiation therapy strategy in a mouse neuroblastoma model: Neuro 2a. An adenovirus encoding a secretable form of GRP94 gene (AdsGRP94) was evaluated in various anti-tumor experiments. Lethally irradiated, virus-infected cells were used as vaccines. Adenoviral vectors were also injected directly into tumors in conjunction with tumor irradiation. The results showed that inoculation of AdsGRP94 infected Neuro 2a cells in syngeneic A/J mouse could result in significant tumor growth delay. Vaccination with lethally irradiated, AdsGRP94-infected Neuro 2a cells completely prevented subsequent tumor growth from challenge inoculations of as many as 107cells/mouse. Splenocytes from mice immunized with AdsGRP94-infected tumor cells showed significant increase in specific tumor cell lytic ability as compared to splenocytes from mice immunized with control-virus infected cells. In addition, intracellular cytokine staining results showed AdsGRP94-infected tumor cells immunization could increase T cell IFN-g generation, especially in CD8+ T cell group. In established tumor models, when vaccination was combined with radiation therapy and intratumoral AdsGRP94 injections, tumor growth was markedly inhibited. Our results indicate that combined AdsGRP94-based immunotherapy and radiation therapy may be a potentially effective strategy for neuroblastoma treatment.