In Vivo Therapy of Hepatocellular Carcinoma with a Tumor-Specific Adenoviral Vector Expressing Interleukin-2

Abstract

A recombinant adenovirus (AdVAFPl-IL2) containing the murine alpha-fetoprotein (AFP) promoter was constructed to direct hepatocellular carcinoma (HCC)-specific expression of the human interleukin-2 (IL-2) gene. In vitro testing of AdVAFPl-IL2 showed HCC-specific IL-2 gene expression three to four orders of magnitude higher in AFP-producing HCC lines compared to non-AFP producing non-HCC lines. The in vivo efficacy and tumor specificity of AdVAFPl-IL2 was evaluated compared to AdVCMV-IL2 (in which the IL-2 gene is driven by the strong constitutive cytomegalovirus promoter) in the treatment of established human HCC (Hep 3B/Hep G2) xenografts growing in CB-17/SCID mice. Intratumoral injection of AdV resulted in growth retardation and regression in a majority of established hepatomas, but with a much wider therapeutic index and less systemic toxicity using the AFP vector. This study illustrates the superiority of using transcriptionally targeted recombinant AdV vectors in cytokine-based gene therapy.

Overview summary

The aim of the present study was to develop a tumor-specific cytokine-based gene therapy model for human hepatocellular carcinoma (HCC). A recombinant adenoviral vector in which the human interleukin-2 (IL-2) gene is under transcriptional regulation of a murine alpha-fetoprotein (AFP) promoter directed HCC-specific expression of this cytokine. In vivo studies utilizing severe combined immu-nodeficient (SCID) mice harboring subcutaneous HCC xenografts demonstrated that intratumoral (IT) delivery of both AdVAFPl-IL2 and Ad-VCMV-IL2 effected growth retardation in all animals tested and some tumor eradication, but a much higher therapeutic index was achieved with AdVAFPl-IL2 at 2 × 10⁹ pfu/dose. The impressive tumor responses observed in this immunodeficient rodent model and the use of an inflammatory cytokine such as IL-2 in this study underscore the potential and limitations of tumor-specific gene therapy for primary HCC.