Cancer Gene Therapy Using Tumor Cells Infected with Recombinant Vaccinia Virus Expressing GM-CSF

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Abstract
The efficacy of a recombinant vaccinia virus (rvv-mGM-CSF) expressing murine granulocyte-macrophage colony stimulating factor (GM-CSF) for use in cancer gene therapy was evaluated. C57BL/6 mice with established B16-F10 melanoma were treated by s.c. injection of irradiated B16 cells infected with two different recombinant vaccinia virus (rvv) constructs. Mice treated with rvv-mGM-CSF vaccine survived longer (p < 0.05), were free of palpable tumors (>4 mm) longer (p < 0.02), and had smaller mean tumor volumes (p < 0.005) compared to those treated with irradiated B16 cells infected with a control rvv (rvv-lacZ) expressing Escherichia coli β-galactosidase or irradiated uninfected B16 cells. The vaccine appeared to be B16 tumor cell specific, because there was no therapeutic effect when heterologous but syngeneic (H-2b) colon adenocarcinoma cells, MC-38 infected with rvv-mGM-CSF were used as vaccine. In this model, rvv expressing interleukin-2 (IL-2) was ineffective. In addition, experimental lung metastasis of B16 tumor cells was significantly inhibited by rvv-mGM-CSF vaccine compared to several control vaccines when the vaccine was applied either by i.p. route (p < 0.006) or by s.c. injection (p < 0.0008). B16 cells expressing mGM-CSF after infection with rvv-mGM-CSF or transduction with a retroviral vector, were equally effective (p > 0.14) as vaccines against lung metastasis. Inhibition of metastasis was also B16 tumor cell specific. These data suggest that this approach of cancer gene therapy has a potential for use in cancer patients. Tumor cells transfected with cDNAs expressing various cytokines have been used as tumor vaccines in several studies. This vaccination showed antitumor effects in some cases. In most of these studies, retroviruses were used as vectors for transfection of the tumor cells. However, for certain applications of gene therapy in cancer, continued expression of the inserted gene from retrovirus constructs is unnecessary. DNA viruses such as adenovirus or vaccinia virus can be used effectively for this purpose. We show here that irradiated B16-F10 melanoma cells infected with recombinant vaccinia virus (rvv) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) can be used for the therapy of small, established tumors. Mice treated with this vaccine survived longer and had smaller mean tumor volumes compared to controls. Lung metastases of melanoma cells were also inhibited by this vaccine. Our data suggest that this approach for gene therapy has potential use in cancer patients.