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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.
AuthorsM Toda, R L Martuza, S D Rabkin
JournalGene therapy (Gene Ther) Vol. 8 Issue 4 Pg. 332-9 (Feb 2001) ISSN: 0969-7128 [Print] England
PMID11313808 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antiviral Agents
  • Cancer Vaccines
  • Interleukin-12
  • Thymidine Kinase
  • Ganciclovir
Topics
  • Adenocarcinoma (immunology, therapy)
  • Animals
  • Antiviral Agents (therapeutic use)
  • Cancer Vaccines (administration & dosage)
  • Colonic Neoplasms (therapy)
  • Cytotoxicity Tests, Immunologic
  • Ganciclovir (therapeutic use)
  • Genetic Therapy (methods)
  • Genetic Vectors (administration & dosage)
  • Herpesvirus 1, Human (enzymology, genetics)
  • Injections, Intralesional
  • Interleukin-12 (genetics)
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental (therapy)
  • Thymidine Kinase (administration & dosage, genetics)
  • Tumor Cells, Cultured

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