title: Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus-based cancer vaccine.
abstract: We have used syngeneic, established bilateral subcutaneous tumor models to examine the antitumor activity of herpes simplex virus (HSV) vectors, including the induction of an immune response against non-inoculated distant tumors. In such a model with CT26 murine colon adenocarcinoma, unilateral intratumoral inoculation of replication-deficient HSV-1 tsK inhibited the growth of both the inoculated and noninoculated established tumors. To enhance this limited antitumor immune response, we generated a defective HSV vector, dvIL12-tk encoding both interleukin-12 (IL-12) and HSV thymidine kinase (TK), with tsK as the helper virus. In a 'suicide gene' strategy, ganciclovir (GCV) treatment after intratumoral inoculation of dvlacZ-tk/tsK, encoding E. coli lacZ instead of IL-12, resulted in enhanced antitumor activity. Antitumor activity was also enhanced by local expression of IL-12 from dvIL12-tk/tsK. The combination of IL-12 cytokine therapy with GCV treatment was the most efficacious approach, with significantly greater inhibition of tumor growth than IL-12 or TK + GCV alone. These results illustrate the power of combining different cancer therapy approaches; 'suicide gene' therapy, cytokine therapy, and HSV vector infection. HSV vectors are particularly well suited to this because they can accommodate the insertion of large and multiple gene sequences.
authors: Department of Neurosurgery, Georgetown University Medical Center, Washington, DC, USA.
authors: M
authors: M
authors: Toda
authors: R L
authors: RL
authors: Martuza
authors: S D
authors: SD
authors: Rabkin
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003110:Colonic Neoplasms / Q000628:therapy; D003601:Cytotoxicity Tests, Immunologic; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy; D013937:Thymidine Kinase / Q000008:administration & dosage / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000998:Antiviral Agents; D019496:Cancer Vaccines; D018664:Interleukin-12; D013937:Thymidine Kinase; D015774:Ganciclovir