Coexpression of Interleukin-4 and B7.1 in Murine Tumor Cells Leads to Improved Tumor Rejection and Vaccine Effect Compared to Single Gene Transfectants and a Classical Adjuvant

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Abstract
To improve the vaccine potency of gene-modified tumor cells, using retroviruses, we have expressed the B7.1 gene in J558L cells and a subline previously transfected with the gene for interleukin-4 (IL-4). Complete long-term tumor eradication occurred in only 73–82% of syngeneic BALB/c mice injected with IL-4 or B7.1 transfectants or tumor cells mixed with the adjuvant Corynebacterium parvum. In contrast, none of the mice injected with J558-IL4/B7.1 cells developed a tumor, thus demonstrating that IL-4 and B7.1 together induced a more potent antitumor immune response compared to either molecule alone. Immunization/challenge experiments demonstrated that IL-4/B7.1 co-transfected cells possessed improved and tumor-specific vaccine potency when compared to single gene transfectants and, more importantly, to a tumor cell/ C. parvum mixture. Furthermore, irradiation of vaccine cells almost completely abrogated the vaccine effect. Together, our results mean a step toward an improved tumor cell vaccine that acquires efficacy by the concerted action of IL-4 and B7.1 and the use of viable cells. The question of whether there is any cytokine that exerts reproducible vaccine potential when tested by immunization experiments with transfected tumor cells is a matter of debate and seems to vary depending on the tumor model. We have previously shown that a variety of cytokine gene (IL-2, IL-4, IL-7, TNF, IFN-γ) -transfected J558L cells or any combination of two always conferred a certain protection against a subsequent lethal tumor challenge that, however, was not superior to a tumor cell/adjuvant (Corynebacterium parvum) vaccine. In this study, we demonstrate that IL-4/B7.1 co-transfected cells are superior as a vaccine compared to a tumor cells/C. parvum mixture. Furthermore, viable cells are superior to irradiated cells as vaccines and transfection of three genes (IL-4, B7.1, and TK) provides a basis for a safe, live, tumor cell vaccine.

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