Different efficacy of in vivo herpes simplex virus thymidine kinase gene transduction and ganciclovir treatment on the inhibition of tumor growth of murine and human melanoma cells and rat glioblastoma cells

Initial studies have demonstrated the therapeutic efficacy for cancer treat ment of in vivo transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir (GCV) treatment. However, recent studies have quest ioned the validity of this approach. Using retroviral vector-producing cell s (VPC) as a source for in vivo gene transfer, we evaluated the efficacy of in vivo transduction of malignant cells using three different tumor cell m odels: B16 murine and IIB-MEL-LES human melanomas and a C6 rat glioblastoma . In vitro studies showed a bystander effect only in CG cells. In vivo stud ies showed an inhibition of tumor growth in the two melanoma models when tu mor cells were coinjected with VPC-producing retroviral vectors carrying th e herpes simplex virus thymidine kinase gene, followed by GCV treatment; ho wever, 100% of mice developed tumors in both models. Under similar experime ntal conditions, 70% (7 of 10) of syngeneic rats completely rejected stereo tactically transferred CG tumor cells; most of them (5 of 10) showed a prol onged survival. Treating established CG rumors with VPC-producing retrovira l vectors carrying the herpes simplex virus thymidine kinase gene and GCV l ed to the cure of 33% (4 of 12) of the animals. Rats that rejected tumor gr owth developed an antitumor immune memory, leading to a rejection of a ster eotactic contralateral challenge with parental cells. The immune infiltrate , which showed the presence of T lymphocytes, macrophages, and polymorphonu clear cells at the site of the first injection and mainly T lymphocytes and macrophages at the site of tumor challenge, strengthened the importance of the immune system in achieving complete tumor rejection.