633. Improved Antitumoral Efficacy of Semliki Forest Virus Vectors Expressing IL-12 in Orthotopic Hepatocellular Carcinoma Models
Authors: Juan R. Rodriguez, Min Guan, Erkuden Casales, Jesus Prieto, Cheng Qian, Cristian Smerdou
Journal: Molecular Therapy (2006)

Semliki Forest virus based vectors expressing interleukin 12 (SFV- IL-12) have shown high antitumoral efficacy in the treatment of solid tumors after intratumoral injection. However, in most cases these tumor models were based on subcutaneous implantation of tumor cells. The aim of this work was to evaluate the antitumoral efficacy of SFV vectors expressing IL-12 in the treatment of orthotopic tumors induced in the liver. McA-RH7777 hepatocellular carcinoma cells were implanted in the liver left lobe of Buffalo rats and when tumor size reached 5–7 mm in diameter animals were treated by intratumoral injection of SFV-IL-12 viral particles (vp). Previous results from our group had shown that in this model a dose of 108 vp of SFV-IL-12 was able to induce 50% of total tumor regressions 30 days after intratumoral injection. In order to improve the efficacy of this treatment we evaluated the antitumoral efficacy of an improved SFV vector able to express IL-12 at levels 8-fold higher (SFV-enhIL-12). In this vector each IL-12 subunit is expressed from independent viral subgenomic promoters fused to the SFV capsid translation enhancer. The administration of 108 vp of SFV- enhIL-12 considerably increased the antitumoral efficacy, since this vector was able to completely eliminate tumor nodules in more than 80% of treated animals. Recombinant IL-12 was detected in the serum of only 33% of the animals on the first day after treatment, being undetectable at longer times, suggesting that IL-12 expression had occurred mainly within the tumor nodule. These results show that the SFV-enhIL-12 vector could be a good candidate to treat solid tumors developed in the liver. Semliki Forest virus based vectors expressing interleukin 12 (SFV- IL-12) have shown high antitumoral efficacy in the treatment of solid tumors after intratumoral injection. However, in most cases these tumor models were based on subcutaneous implantation of tumor cells. The aim of this work was to evaluate the antitumoral efficacy of SFV vectors expressing IL-12 in the treatment of orthotopic tumors induced in the liver. McA-RH7777 hepatocellular carcinoma cells were implanted in the liver left lobe of Buffalo rats and when tumor size reached 5–7 mm in diameter animals were treated by intratumoral injection of SFV-IL-12 viral particles (vp). Previous results from our group had shown that in this model a dose of 108 vp of SFV-IL-12 was able to induce 50% of total tumor regressions 30 days after intratumoral injection. In order to improve the efficacy of this treatment we evaluated the antitumoral efficacy of an improved SFV vector able to express IL-12 at levels 8-fold higher (SFV-enhIL-12). In this vector each IL-12 subunit is expressed from independent viral subgenomic promoters fused to the SFV capsid translation enhancer. The administration of 108 vp of SFV- enhIL-12 considerably increased the antitumoral efficacy, since this vector was able to completely eliminate tumor nodules in more than 80% of treated animals. Recombinant IL-12 was detected in the serum of only 33% of the animals on the first day after treatment, being undetectable at longer times, suggesting that IL-12 expression had occurred mainly within the tumor nodule. These results show that the SFV-enhIL-12 vector could be a good candidate to treat solid tumors developed in the liver.