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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

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Abstract

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.

Materials and 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.

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Acknowledgments

We thank T. Boon for MAGE-1 and MAGE-3 complementary DNA clones and C. Gee for B16 tat cells. CD4−/− and CD8−/− mice were a kind gift of T. Mak. This work was supported by grants of the Schweizerische Nationalfonds (823A–037047) and the Roche Research Foundation (95–134) to HB and a grant of the National Cancer Institute (NCI CA63399) to RCM.

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  1. Howard Hughes Medical Institute, Children’s Hospital and Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts, 02115, USA

    Hansruedi Büeler & Richard C. Mulligan

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Büeler, H., Mulligan, R.C. 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. Mol Med 2, 545–555 (1996). https://doi.org/10.1007/BF03401639

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