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

Abstract

Transduction of the murine interferon-alpha (IFN-alpha) 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-alpha-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-alpha-producing FLC, which occasionally lead to the formation of slowly growing tumors; and, that (ii) repeated injections of irradiated IFN-alpha-FLC did not result in any antitumor effect. The therapeutic potential of IFN-alpha-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 > or = 70% of the animals after injection of high numbers (10(7)) of IFN-alpha-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.

Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine

“…[6][7][8] In our treatment model, vaccination with nonirradiated 9L-IL4 tumor cells was found to be significantly more effective in increasing survival in Fischer rats with established intracranial tumors when compared with repetitive vaccination with irradiated IL-4 expressing tumor cells (P = 0.0111). This observation is consistent with other investigators' findings [26][27][28] and provides a rationale for the clinical use of nonirradiated tumor vaccines.…”

Recombinant interferon α2a synergistically enhances ganciclovir-mediated tumor cell killing in the herpes simplex virus thymidine kinase system

“…In one example, immunization to tumor cells before treatment with the HSV-TK gene-modified cells and GCV resulted in prolonged animal survival. 14 Our results confirm and extend previous findings using IFN 15,16 by demonstrating the importance of this combination in a therapeutic tumor model and analyzing the underlying mechanism that leads to a synergistic antitumor effect. We have demonstrated that a low dose of IFN␣2a decreased the IC 50 of GCV from 0.03 M to 0.005 M in PA1STK cells.…”

Adenovirus-mediated lymphotactin gene transfer improves therapeutic efficacy of cytosine deaminase suicide gene therapy in established murine colon carcinoma

“…Various cytokine genes, including GM-CSF, IL-2, IL-4, IFN-␣ and IFN-␥ have been transferred into tumor cells in combination with HSVtk or CD suicide gene therapy, and more potent antitumor effects and more efficient induction of antitumor immune response have been observed with these combination therapies. [12][13][14][29][30][31][32][33] In this investigation, we first explored the antitumor efficacy of chemokine gene transfer in combination with CD/5FC gene therapy. Chemokines are pivotal in the trafficking of leukocytes.…”