Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus

Herpes simplex virus type 1 (HSV-1) replication within tumors can mediate t umor regression (oncolysis). The genetically engineered, HSV-1 mutant rRp45 0 does not express viral ribonucleotide reductase and is therefore replicat ion conditional. During the course of infection, rRp450 expresses the cytoc hrome P450 transgene and HSV-1 thymidine kinase gene, thereby enabling it t o bioactivate the prodrugs cyclophosphamide and ganciclovir, respectively. rRp450 replication in hepatocellular carcinoma (HCC) cells is cytotoxic and liberates progeny virion that infect adjacent tumor cells. rRp450-mediated oncolysis is enhanced in the presence of cyclophosphamide, whereas it is i nhibited in the presence of ganciclovir. As a consequence of defective vira l ribonucleotide reductase expression, the yield of rRp450 progeny virions from infection of HCC cells is 3 to 4 log orders greater than that from inf ection of normal hepatocytes. This is associated with dramatic tumor reduct ion of diffuse HCC after a single intravascular administration of rRp450. r Rp450 holds the promise of the dual therapeutic benefit of selective oncoly sis and P450 transgene delivery.