A conditionally replicative adenovirus is a novel
anticancer agent designed to replicate selectively in
tumor cells. However, a leak of the virus into systemic circulation from the
tumors often causes ectopic
infection of various organs. Therefore, suppression of naive viral tropism and addition of
tumor-targeting potential are necessary to secure patient safety and increase the
therapeutic effect of an oncolytic adenovirus in the clinical setting. We have recently developed a direct selection method of targeted vector from a
random peptide library displayed on an adenoviral fiber knob to overcome the limitation that many cell type-specific
ligands for targeted adenovirus vectors are not known. Here we examined whether the addition of a
tumor-targeting
ligand to a replication-competent adenovirus ablated for naive tropism enhances its therapeutic index. First, a
peptide-display adenovirus library was screened on a
pancreatic cancer cell line (AsPC-1), and particular
peptide sequences were selected. The replication-competent adenovirus displaying the selected
ligand (AdDeltaCAR-SYE) showed higher oncolytic potency in several other
pancreatic cancer cell lines as well as AsPC-1 compared with the untargeted adenovirus (AdDeltaCAR). An intratumoral injection of AdDeltaCAR-SYE significantly suppressed the growth of AsPC-1 subcutaneous
tumors, and an analysis of adenovirus titer in the
tumors revealed an effective replication of the virus in the
tumors. Ectopic liver gene transduction following the intratumoral injection of AdDeltaCAR-SYE was not increased compared with the AdDeltaCAR. The results showed that a
tumor-targeting strategy using an adenovirus library is promising for optimizing the safety and efficacy of oncolytic adenovirus
therapy.