Abstract
A plasmid expression system encoding murine IFN-α4 and complexed with a protective interactive noncondensing polymeric (PINC) delivery system was used for in vivo immunotherapy treatment of an immunogenic murine renal cell carcinoma, Renca, and a nonimmunogenic mammary adenocarcinoma, TS/A. Mice bearing established tumors were treated with IFN-α/polyvinylpyrrolidone (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 μg of formulated IFN-α 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-α 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-α/PVP treatments. Finally, mice that remained tumor free following IFN-α gene therapy displayed immune resistance to a subsequent tumor challenge. These data provide evidence that IFN-α gene therapy can be used to induce an efficient antitumor response in vivo.
Overview summary
The local presence of cytokines in tumors can activate an immune response that in some cases leads to induction of long-lasting tumor-specific immunity. By direct intratumoral injection of plasmid encoding murine IFN-α4 in a PINC delivery system, tumor-bearing mice develop an immune response, which leads to inhibition of tumor growth. We show here by performing depletion studies in vivo that the immune response induced by IFN-α is primarily mediated by CD8+ T cells and that this therapy results in a long-term immunity in mice demonstrating complete tumor regression. Thus, nonviral IFN-α gene therapy may be an effective alternative to IFN-α protein therapy for human cancers.
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