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.
Mullen
C A
CA
Department of Experimental Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Anderson
L
L
Woods
K
K
Nishino
M
M
Petropoulos
D
D
D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology; D003601:Cytotoxicity Tests, Immunologic; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods; D007150:Immunohistochemistry; D051379:Mice; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000276:immunology; D018139:Simplexvirus / Q000201:enzymology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D003520:Cyclophosphamide; D013937:Thymidine Kinase; D015774:Ganciclovir