Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines

We have directly compared the efficacy of two immunotherapeutic strategies for the treatment of cancer: "vaccination" of tumor-bearing mice with genet ically modified dendritic cells (DCs), and vaccination with genetically mod ified tumor cells. Using several different preexisting tumor models that ma ke use of B16F10 melanoma cells expressing a target tumor antigen (human me lanoma-associated gene [MAGE]-1), we found that vaccination with bone marro w-derived DCs engineered to express MAGE-1 via adenoviral-mediated gene tra nsfer led to a dramatic decrease in the number of metastases in a lung meta stasis model, and led to prolonged survival and some long-term cures in a s ubcutaneous preexisting tumor model. In contrast, Vaccination with granuloc yte/macrophage colony-stimulating factor (GM-CSF)-transduced tumor cells, p reviously shown to induce potent antitumor immunity in standard tumor chall enge assays, led to a decreased therapeutic effect in the metastasis model and no effect in the subcutaneous tumor model. Further engineering of DCs t o express either GM-CSF, tumor necrosis factor alpha, or CD40 ligand via re troviral-mediated gene transfer, led to a significantly increased therapeut ic effect in the subcutaneous tumor model. The immunological mechanism, as shown for GM-CSF-transduced DCs, involves MAGE-1-specific CD4(+) and CD8(+) T cells. Expression of GM-CSF by DCs led to enhanced cytotoxic T lymphocyt e activity, potentially mediated by increased numbers of DCs in draining ly mph nodes. Our results suggest that clinical studies involving the vaccinat ion with genetically modified DCs may be warranted.