Combined suicide and granulocyte-macrophage colony-stimulating factor genetherapy induces complete tumor regression and generates antitumor immunity

The use of prodrug-activated ("suicide") gene therapy has been shown to be effective in inducing tumor regression when only a small proportion of turn er cells contains the suicide gene. These experiments were designed to test whether additional therapeutic benefit may be obtained by stimulating the immune response. Murine MC26 colon carcinoma cells, either untransduced or transduced with genes for herpes simplex virus-1 thymidine kinase (HSV1-TK) or human GM-CSF, were injected subcutaneously into syngeneic BALB/c mice i n various combinations. Inoculation of equal numbers of untransduced and HS V1 -TK-containing cells Followed by ganciclovir (GCV) treatment resulted in almost complete tumor regression, but by 7 weeks, tumors had recurred in a ll mice. A similar initial regression was obtained using equal numbers of c ells containing HSV1-TK and GM-CSF genes, but > 80% of these mice remained tumor-free after 3 months. Groups of tumor-free mice that had received CM-C SF-containing cells were left for different periods of time and rechallenge d with unmodified MC26 cells on the opposite flank. Of the mice rechallenge d 14, 28, and 108 days later, 100%, 88%, and 57%, respectively, showed comp lete resistance to unmodified tumor cells. In mice that showed tumor regrow th, tumor volume was much less than in control mice. Adoptive transfer of s pleen cells from resistant mice to naive syngeneic mice resulted in partial resistance to challenge with unmodified tumor cells. Specific cytotoxicity against MC26 cells was only demonstrable in mice receiving GM - CSF- and H SV1 -TK-containing tumor cells. These experiments show that the presence of cells secreting CM-CSF in HSV1 -TK-containing, regressing tumor is able to induce complete or partial resistance to tumor rechallenge. This indicates the potential usefulness of GM-CSF in enhancing other antitumor therapies.