255. Potent Cancer Immunotherapy with Dendritic Cells Generated from Genetically Modified Hematopoietic Stem Cells

Abstract

Top of pageAbstract Many cancer gene therapy strategies rely upon the ability to deliver genes to tumors in vivo leading to the direct killing of tumor cells. We have shown previously, using the B16/HSVtk melanoma model, that in situ tumor cell death can be immunogenic due to recruitment, loading and activation of antigen presenting cells with released tumor antigens. We have now focused upon combining gene therapy with other therapeutic modalities to increase the efficacy of either alone in an attempt to compensate for the poor efficiency of gene delivery. Therefore, we have studied the effects of killing tumors with the HSVtk system to generate an inflammatory environment in vivo to enhance the recruitment of adoptively transferred T cells to the tumor site. We hypothesized that a local inflammatory response at the tumor site should incorporate production of cytokines and chemokines that will enhance the recruitment of adoptively transferred activated T cells. To our surprise, adoptive transfer of ova-specific activated CD8 T cells during the time of GCV treatment did not influence tumor progression. In vitro studies revealed that the supernatant from GCV-treated tumor cells caused death of activated T cells. For this reason, in vivo experiments were repeated with adoptive transfer of ova-specific activated CD8 T two days after GCV treatment. Under these conditions adoptive transfer enhanced the survival of GCV-treated mice. These studies indicate that additive effects can be obtained from the combination of adoptive transfer and local inflammation achieved via gene transfer of the HSVtk gene into tumors. However, our studies also reveal that the HSVtk/GCV strategy may have potentially adverse effects on infiltrating immune cells. Therefore, careful timing of the application of gene therapy with T cell adoptive therapy will be required to optimize the benefits of the combination.