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

ABSTRACT

We have directly compared the efficacy of two immunotherapeutic strategies for the treatment of cancer "vaccination" of tumor-bearing mice with genetically modified dendritic cells (DCs), and vaccination with genetically modified tumor cells. Using several different preexisting tumor models that make use of B16F10 melanoma cells expressing a target tumor antigen (human melanoma-associated gene [MAGE]-1), we found that vaccination with bone marrow-derived DCs engineered to express MAGE-1 via adenoviral-mediated gene transfer led to a dramatic decrease in the number of metastases in a lung metastasis model, and led to prolonged survival and some long-term cures in a subcutaneous preexisting tumor model. In contrast, vaccination with granulocyte/macrophage colony-stimulating factor (GM-CSF)-transduced tumor cells, previously shown to induce potent antitumor immunity in standard tumor challenge assays, led to a decreased therapeutic effect in the metastasis model and no effect in the subcutaneous tumor model. Further engineering of DCs to express either GM-CSF, tumor necrosis factor alpha, or CD40 ligand via retroviral-mediated gene transfer, led to a significantly increased therapeutic 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 lymphocyte activity, potentially mediated by increased numbers of DCs in draining lymph nodes. Our results suggest that clinical studies involving the vaccination with genetically modified DCs may be warranted.