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 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.
Klein
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Howard Hughes Medical Institute, Children's Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bueler
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Mulligan
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D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology
D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D016827:CD8 Antigens; D019496:Cancer Vaccines; C072011:MAGEA1 protein, human; C489518:Mageb1 protein, mouse; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor