Nonviral interferon α gene therapy inhibits growth of established tumors by eliciting a systemic immune response

A plasmid expression system encoding murine IFN-alpha 4 and complexed with a protective interactive noncondensing polymeric (PINC) delivery system was used for in vivo immunotherapy treatment of an immunogenic murine renan cell carcinoma, Renca, and a nonimmunogenic mammary adenocarcinoma, TS/A, Mice bearing established tumors were treated with IFN-alpha/polyvinylpyrrdidone (PVP) expression complexes via direct intratumoral injection. Up to 100% inhibition of tumor growth was observed in the treated mice. By using an optimal dose of 96 and 48 mu g of formulated IFN-alpha plasmid for the treatment of Renca and TS/A, respectively, 30% (Renca) and 10% (TS/A) of the treated animals remained tumor free. Inhibition of tumor growth was dependent on activation of the immune system. The antitumor activity elicited by IFN-alpha gene therapy was abrogated when mice were selectively depleted of CD8(+) T cells. By contrast, depletion of CD4(+) T cells resulted in enhanced tumor rejection following IFN-alpha/PVP treatments. Finally, mice that remained tumor free following IFN-alpha gene therapy displayed immune resistance to a subsequent tumor challenge. These data provide evidence that IFN-alpha gene therapy can be used to induce an efficient antitumor response in vivo.