Nonviral interferon alpha gene therapy inhibits growth of established tumors by eliciting a systemic immune response.
A plasmid expression system encoding murine IFN-alpha4 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-alpha/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 microg 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.
Coleman
M
M
GeneMedicine, Inc., The Woodlands, TX 77381-4248, USA.
Muller
S
S
Quezada
A
A
Mendiratta
S K
SK
Wang
J
J
Thull
N M
NM
Bishop
J
J
Matar
M
M
Mester
J
J
Pericle
F
F
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000818:Animals; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D010957:Plasmids / Q000235:genetics; D011205:Povidone; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D011205:Povidone