Dendritic cells augment granulocyte-macrophage colony-stimulating factor (GM-CSF)/herpes simplex virus thymidine kinase-mediated gene therapy of lung cancer.

Lung cancer, the leading cause of cancer death in the United States, is resistant to most currently available therapies. To evaluate a multicomponent gene therapy approach that replaces tumor-bearing host immune deficits, we genetically modified Line 1 (L1C2), a weakly immunogenic alveolar cell carcinoma cell line. L1C2 was transduced ex vivo with a retroviral construct that contained two components: a cytokine gene (granulocyte-macrophage colony-stimulating factor) and a drug sensitivity gene (herpes simplex virus thymidine kinase). The third component of this therapy, in vitro-activated syngeneic bone marrow-derived dendritic cells, was included to augment antigen presentation. The addition of ganciclovir (GCV) caused the lysis of transduced tumor cells, resulting in the release of potential tumor antigens. Ex vivo-transduced tumor cells regressed in vivo following GCV therapy but were not effective in the treatment of established parental tumors. To treat established tumors, dendritic cells were administered in combination with transduced tumor cells and GCV. A total of 50% of these mice rejected the 5-day-old established tumors and were immune to rechallenge with parental L1C2 cells. Thus, this multicomponent gene therapy system leads to both the regression of established tumors and enhanced immunogenicity in this weakly immunogenic murine lung cancer model.