Safety and antitumor effect of oncolytic and helper-dependent adenoviruses expressing interleukin-12 variants in a hamster pancreatic cancer model.

摘要: Gene transfer of potent immunostimulatory cytokines such as interleukin-12 (IL-12) is a potential treatment for advanced cancer. Different vectors and IL-12 modifications have been developed to avoid side effects associated with high serum levels the cytokine, while preserving its antitumor properties. Here we evaluated two alternative strategies using Syrian hamster model pancreatic cancer metastatic liver. Local administration an oncolytic adenovirus (OAV) expressing single-chain version caused transient, very intense elevations in serum, resulting severe toxicity at sub-therapeutic doses. Anchoring membrane infected cells by fusion transmembrane domain CD4 reduced systemic exposure increased tolerance OAV. However, only modest increase therapeutic range was achieved because potency also reduced. In contrast, helper-dependent adenoviral vector (HDAd) equipped Mifepristone-inducible expression system allowed sustained controlled production from This well tolerated inhibited progression hepatic metastases. We conclude that HDAds are safer than OAVs delivery IL-12, promising immunogene therapy approaches against