Intravenous Cytokine Gene Delivery by Lipid-DNA Complexes Controls the Growth of Established Lung Metastases

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Abstract
Local expression of cytokine genes by ex vivo transfection or intratumoral gene delivery can control the growth of cutaneous tumors. However, control of tumor metastases by conventional nonviral gene therapy approaches is more difficult. Intravenous injection of lipid-DNA complexes containing noncoding plasmid DNA can significantly inhibit the growth of early metastatic lung tumors. Therefore, we hypothesized that delivery of a cytokine gene by lipid-plasmid DNA complexes could induce even greater antitumor activity in mice with established lung metastases. The effectiveness of treatment with lipid-DNA complexes containing the IL-2 or IL-12 gene was compared with the effectiveness of treatment with complexes containing noncoding (empty vector) DNA. Treatment effects were evaluated in mice with either early (day 3) or late (day 6) established lung tumors. Lung tumor burdens and local intrapulmonary immune responses were assessed. Treatment with either noncoding plasmid DNA or with the IL-2 or IL-12 gene significantly inhibited the growth of early tumors. However, only treatment with the IL-2 or IL-12 gene induced a significant reduction in lung tumor burden in mice with more advanced metastases. Furthermore, the reduction in tumor burden was substantially greater than that achieved by treatment with recombinant cytokines. Treatment with the IL-2 or IL-12 gene was accompanied by increased numbers of NK cells and CD8+ T cells within lung tissues, increased cytotoxic activity, and increased local production of IFN-gamma by lung tissues, compared with treatment with noncoding DNA. Thus, cytokine gene delivery to the lungs by means of intravenously administered lipid-DNA complexes may be an effective method of controlling lung tumor metastases.