Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes

Current treatment of osteosarcoma produces disappointing outcomes, and inno vative therapies must be investigated. We have used retroviral vectors to t ransfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and exp ressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibili ty to transduced cells. A strong bystander effect was observed in vitro, wh ereby nontransduced tumor cells in proximity to transduced cells acquired s usceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosa rcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector pr oducer cells developed into tumors that completely regressed upon administr ation of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with co mplete tumor ablation when as little as 10% of the cells were HSVtk(+). A s ignificant (P < .05) antitumoral response was seen against primary tumors c omposed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of tre atment. A significant (P < .03) antitumoral response was seen in the treatm ent of established osteosarcomas by the injection of HSVtk vector producer cells.