Induction of antigen-specific tumor immunity by genetic and cellular vaccines against MAGE: enhanced tumor protection by coexpression of granulocyte-macrophage colony-stimulating factor and B7-1.
BACKGROUND
A number of tumors express antigens that are recognized by specific cytotoxic T cells. The normal host immune responses, however, are not usually sufficient to cause tumor rejection. Using appropriate immunization strategies, tumor-specific antigens may serve as targets against which tumor-destructive immune responses can be generated. MAGE-1 and MAGE-3 are two clinically relevant antigens expressed in many human melanomas and other tumors, but not in normal tissues, except testis. Here, we have investigated whether DNA and cellular vaccines against MAGE-1 and MAGE-3 can induce antigen-specific anti-tumor immunity and cause rejection of MAGE-expressing tumors.


METHODS
Mice were immunized against MAGE-1 and MAGE-3 by subcutaneous injection of genetically modified embryonic fibroblasts or intramuscular injection of purified DNA. Mice were injected with lethal doses of B16 melanoma cells expressing the corresponding MAGE antigens or the unrelated protein SIV tat, and tumor development and survival were monitored.


RESULTS
Intramuscular expression of MAGE-1 and MAGE-3 by plasmid DNA injection and subcutaneous immunization with syngeneic mouse embryonic fibroblasts transduced with recombinant retroviruses to express these antigens induced specific immunity against tumors expressing MAGE-1 and MAGE-3. Both CD4+ and CD8+ T cells were required for anti-tumor immunity. Coexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) or B7-1 significantly increased anti-tumor immunity in an antigen-specific manner and resulted in a considerable proportion of mice surviving lethal tumor challenge.


CONCLUSIONS
Our results suggest that genetic and cellular vaccines against MAGE and other tumor antigens may be useful for the therapy of tumors expressing specific markers, and that GM-CSF and B7-1 are potent stimulators for the induction of antigen-specific tumor immunity.
Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts, USA.
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Büeler
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Mulligan
D000818:Animals; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen / Q000235:genetics*; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D007111:Immunity, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D019496:Cancer Vaccines; C489518:Mageb1 protein, mouse; C489519:Mageb3 protein, mouse; D009363:Neoplasm Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor