Ganciclovir Chemoablation of Herpes Thymidine Kinase Suicide Gene-Modified Tumors Produces Tumor Necrosis and Induces Systemic Immune Responses

The goal of this work was to identify potential host immune responses to thymidine kinase (TK) suicide gene-modified tumors undergoing chemoablation induced by the prodrug ganciclovir (GCV). The aims were to measure the efficacy and specificity of immunity induced against unmodified tumor, to identify qualitative or quantitative changes in the host response to TK⁺ tumors undergoing chemoablation that may contribute to the induction of antitumor immunity, and to compare critically the induction of immunity by chemoablation of TK-modified tumors with that of other methods of immunization in this tumor model and in response to other well-defined model antigens. Animals treated with TK⁺ tumors and GCV developed specific resistance to rechallenge with unmodified tumor. GCV induced significant tumor necrosis, which was associated with a pronounced host cell infiltrate composed of polymorphonuclear cells, both CD4⁺ and CD8⁺ T lymphocytes, and increased intratumoral IL-12. Cyclophosphamide-treated mice exhibited no such host response despite the induction of tumor necrosis. CTL responses to defined antigens in TK⁺ cells were greater in animals treated with prodrug than were those in animals not treated with prodrug but harboring live TK⁺ cells. Similar degrees of immunity were produced by immunization with irradiated cells.

Overview summary

Transfer of metabolic suicide genes to tumors and subsequent treatment with prodrug can induce tumor regression in vivo. The antitumor effect is explained largely by the activation of prodrug in the tumor, but an immunological host response to the process may also occur. This work explores the immunological consequences of ganciclovir prodrug ablation of tumor cells modified to express the herpes simplex thymidine kinase gene. Induction of immunity to unmodified tumor, as well as to two defined model antigens on the tumor, was detected. Treatment induced tumor necrosis and a host response consisting of both CD4⁺ and CD8⁺ T cells, polymorphonuclear cells, and IL-12. Such a host response was not seen in animals treated with cyclophosphamide, a commonly used anticancer drug.