The Immune Response Elicited by Mammary Adenocarcinoma Cells Transduced with Interferon- γ and Cytosine Deaminase Genes Cures Lung Metastases by Parental Cells

The parental cells of the TSA murine mammary adenocarcinoma (TSA-pc) were transfected with both the interferon-γ (IFN-γ) gene and the cytosine deaminase (CD) suicide gene to obtain a therapeutic vaccine active against TSA-pc lung metastases. Even in the absence of treatment with the prodrug 5-fluorocytosine (5-FC), the local growth of double transfectants (CD-γ clones) was inhibited by a marked recruitment of granulocytes and macrophages. In mice harboring TSA-pc micrometastases, therapeutic vaccination with either IFN-γ or CD single transfectants reduced the number of lung nodules, whereas CD-γ double transfectants abrogated metastasis growth in up to 80% of mice. Treatment of mice with 5-FC did not alter the curative efficacy of CD-γ double-transfectant cells. By contrast, in mice vaccinated with CD single-transfectant cells, 5-FC treatment caused a significant loss of their curative activity. Host T cells played an active role in the cure of lung metastases, because vaccination of nude mice with CD-γ cells was uneffective.

Overview summary

Metabolic suicide genes are often used to confer drug sensitivity, but their products can also stimulate immune responses. We engineered murine tumor cells both with a suicide gene (Escherichia coli cytosine deaminase) and with a gene for an immunostimulatory cytokine (murine interferon-γ). Double transfectants elicited a local reaction that prevented tumor growth even in the absence of prodrug treatment. Up to 80% of mice bearing lung micrometastases of the parental, nontransduced tumor were cured by the systemic T cell response elicited by vaccination with double-transfectant cells.