Highly efficient transduction and expression of cytokine genes in human tumor cells by means of autonomous parvovirus vectors; Generation of antitumor responses in recipient mice

The possible use of recombinant autonomous parvoviruses as vectors to effic iently express therapeutic cytokines in human tumor cells was evaluated in vitro and in vivo. The parvovirus H1 was used to generate recombinant virus es (rH1) that carried transgenes encoding either human interleukin 2 (IL-2) or monocyte chemotactic protein 1 (MCP-1), in replacement of part of the c apsid genes. Such rH1 viruses have been shown to retain in vitro the intrin sic oncotropic properties of the parental virus. On infection with the reco mbinant viruses at an input multiplicity of 1 replication unit (RU) per cel l, HeLa cultures were induced to release 4-10 mu g of cytokine per 10(6) ce lls over a period of 5 days. The expression of the rH1-transduced human cyt okine/chemokine could also be detected in tumor material recovered from nud e mice that had been subcutaneously engrafted with in vitro-infected HeLa c ells. The formation of tumors from HeLa xenografts was reduced by 90% compa red with wild-type or mock-infected cells Its a result of cells preinfected with IL-2-expressing virus at an input multiplicity as low as 1 RU per cel l. Tumors arising from HeLa cells infected with transgene-free or MCP1-expr essing vectors or with wild-type H1 virus were not rejected at this virus d ose. Tumors infected with rH1/IL-2 virus displayed markers indicative of th eir infiltration with NK cells in which the cytocidal program was activated , whereas little NK activity was detected in wild-type virus or mock-infect ed tumors. Altogether, these data show that the IL-2 expressing H1 vector w as a more potent antineoplastic agent than the parental virus, and point to the possible application of recombinant autonomous parvoviruses toward the rapy of some human tumors.