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.