Cure of Mice with Established Metastatic Friend Leukemia Cell Tumors by a Combined Therapy with Tumor Cells Expressing Both Interferon-α1 and Herpes Simplex Thymidine Kinase Followed by Ganciclovir

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Abstract
Transduction of the murine interferon-α(IFN-α) gene into various malignant mouse tumor cells has resulted in the loss of tumorigenicity and an acquired capacity to induce long-lasting antitumor immunity following their injection into immunocompetent syngeneic mice. In the present study, we investigated the effectiveness of IFN-α-producing tumor cells in the therapy of mice with established mouse tumors. In DBA/2 mice bearing subcutaneous (s.c.) Friend erythroleukemia cell (FLC) tumors, we found that to achieve some antitumor response (i) it was necessary to inject high numbers of IFN-α-producing FLC, which occasionally lead to the formation of slowly growing tumors; and, that (ii) repeated injections of irradiated IFN-α-FLC did not result in any antitumor effect. The therapeutic potential of IFN-α-producing FLC rendered sensitive to ganciclovir (GCV), by transfer of the herpes simplex virus thymidine kinase (tk) gene, was investigated. Complete tumor rejection and cure was observed in ≥70% of the animals after injection of high numbers (107) of IFN-α-producing tk-expressing tumor cells followed 4 days later by repeated GCV treatments, whereas only a slight increase in survival time was obtained after administration of control tk-expressing tumor cells (not producing IFN) and GCV. Tumor rejection was associated with a dramatic destruction of tumor tissue and with the subsequent development of a potent and long-lasting antitumor immunity. No therapeutic effect was observed in immunosuppressed nude mice. These data indicate that this approach may represent an effective and safe therapeutic strategy for antitumor cytokine gene therapy. Live cytokine-producing tumor cells can prove to be more effective in the therapy of established tumors than their irradiated or mitomycin-treated counterparts. However, the possibility of an autonomous growth of viable cytokine-producing tumor cells represents the major drawback for their use as adjuvant therapy of cancer. Live cytokine-producing tumor cells rendered specifically sensitive to drug-induced cytotoxicity could represent a very useful tool for the development of safe and effective strategies in cancer treatment. We report that treatment of immunocompetent mice bearing established metastatic Friend leukemia virus (FLC) tumors with tumor cells expressing both IFN-α and tk, followed by ganciclovir (GCV) administration results in cure of the large majority of the animals. These results represent the first example of a successful therapy of established tumors by combined treatment with cytokine-producing tumor cells genetically modified to express selectively a specific drug sensitivity and subsequent drug administration.

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