Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy

Abstract

Fms-like tyrosine kinase 3 ligand (Flt3L) plays an important role in development and activation of dendritic cells (DCs) and natural killer cells (NK). It has been shown that administration of either tumor cells transfected in vitro with Flt3L vectors or soluble Flt3L fusion protein in a high dose can enhance host antitumor immunity in animal model systems. In this study, we developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter and investigated its biological efficacy in eliciting tumor-specific immune response against hepatocellular carcinoma in mouse hepatoma model. The constructed Ad-mFlt3L efficiently infected hepa 1-6 hepatoma cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCsNK cells and lymphocytes in local tumor tissues. Tumor cells infected with Ad-mFlt3L lost tumorigenicity and became more immunogenic in syngeniec animal models. Intratumoral injection of Ad-mFlt3L (10(9) expression-forming unit) x 3 significantly inhibited tumor growth with elicitation of long-lasting antitumor immunity, which is both preventive and curative. The tumor-specific immunity can be partially abrogated by depletion of either CD3+CD4+ T cells or NK cells and can be also re-established in naïve animals by adoptive transfer of splenocytes from treated mice. The results suggest that adenovirus-mediated Flt3L gene therapy may provide a useful strategy for treatment of cancers.