Nonviral InterferonαGene Therapy Inhibits Growth of Established Tumors by Eliciting a Systemic Immune Response

Abstract

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.

Regression of tumors by IFN-α electroporation gene therapy and analysis of the responsible genes by cDNA array

“…In addition, electroporation delivery reduced both the IFN-␣ dose intensity and the number of administrations for inhibiting tumor growth when compared with other delivery methods. For example, three administrations of adenovirus-IFN-␣2b are required to regress tumor growth, 11 a total of eight administrations of polyvinylpyrrolidone (PVP)-formulated IFN-␣ (48 or 96 g DNA) twice a week are required to regress tumor growth, 9 and a daily administration of recombinant IFN-␣ protein for several weeks is required to inhibit tumor growth. 17 In our study, three administrations of 20 g of IFN-␣ DNA at a 5-day interval either eradicated tumors or inhibited tumor growth.…”

“…40 The therapeutic gene construct, IFN-␣ was provided by Valentis (The Woodlands, TX, USA), and the structure of the construct is depicted in a previous publication. 9 The control construct is the result of a deletion of IFN-␣ cDNA.…”

“…3 Although ex vivo IFN-␣ gene therapy has demonstrated tumor inhibition and elicited tumor-specific immune memory, [4][5][6][7][8] this approach is patient-specific and time-consuming. Direct intratumoral injection of IFN-␣ DNA to treat solid Renca, 9 basal cell carcinoma, 10 and hetero-xenograft prostatic (PC-3) or hepatocellular carcinoma (Hep3B) 11 with the use of viral or liposome-based nonviral delivery systems has effectively suppressed tumors in in vivo mouse models. Intratumoral delivery of the IFN-␣ gene using a simple, powerful approach -electroporation -to treat tumors, however, has not been studied.…”

Biodegradable polymer-based interleukin-12 gene delivery: role of induced cytokines, tumor infiltrating cells and nitric oxide in anti-tumor activity

“…12,13 However, their antiproliferative effects in conjunction with IL-12 and other prominent Th1 type cytokines are still controversial. To confirm whether there is any change in the levels of IFN-␣ after intratumoral injections of PAGA/pCMVmIL-12, PAGA/pmIL-12 complexes and pmIL-12 into the subcutaneous CT-26 tumorbearing mice, we determined the levels of mIFN-␣ by ELISA.…”

A Semliki Forest virus vector engineered to express IFNα induces efficient elimination of established tumors

“…11 Several approaches for the delivery of the IFNa gene to tumor cells have been tested including non-viral and viral vectors. [12][13][14][15][16] In these studies, intratumoral delivery of IFNa has led to potent antitumor effects, which were mediated by the immunostimulatory capacity of this cytokine. 12,17,18 Semliki Forest virus (SFV) belongs to the Alphavirus genus, which comprises enveloped viruses carrying a single positive-strand RNA genome of about 12 kb.…”