Complementary adenoviral vectors for oncolysis

Replication-competent adenoviruses (Ads) were used for oncolytic virotherap y soon after they were discovered. Recently mutated and genetically enginee red Ads have been shown to selectively lyse tumor cells. We have split the human Ad type 5 genome into two defective viruses that complement each othe r only in certain tumor cells. The genome of one of these vectors, GT5610, contains only the minimal viral elements required in cis for replication an d packaging and the E1 viral genes with E1A under the control of the human alpha-fetoprotein promoter. This "controlled" vector has a capacity for 30 kilobases of foreign DNA. The supplemental vector, AdH beta, contains all a denoviral genes except for E1. Both vectors were designed to carry heterolo gous reporter genes whose expression could be detected throughout the tumor . Coinfection of hepatocarcinoma cells that have the capacity to transcribe genes under the control of the alpha-fetoprotein promoter leads to cell ly sis and copropagation. The oncolytic spread of these complementary vectors in vivo was demonstrated by the intratumoral injection of human hepatocarci nomas xenografted in severe combined immunodeficient (SCID) mice. This syst em presents safety and gene capacity features that could yield a therapeuti c advantage over oncolysis by a single virus.