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

Abstract

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.

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

“…The bystander effect is believed to be mediated partly by the transfer of phosphorylated compounds, via gap junctions, into neighboring cells, 14 ± 17 and partly by local immune responses. 1,18,19 Several studies have demonstrated the immunological component of the bystander effect. Nude mice are impaired in their ability to effect suicide gene -mediated tumor regression, 8,12 treatment generates systemic antitumor immunity, 8,20,21 and tumor regression is associated with a significant leukocytic infiltrate 11,19,22,23 and cytokine release.…”

Potentiation of antitumor immunity by antibody-directed enzyme prodrug therapy

“…Treatment of tk-or CD-transduced tumors with GCV or 5-FC in many instances produced similar antitumor immunity as immunization with radiation-or drug-treated tumor cells, 39,40 only weak or no CTL activity after prodrug treatment of tumors 37,41,42 and incomplete 29,39 or no 43,44 protective immunity. ADEPT, in contrast, generated long-lasting systemic antitumor immunity that could not be generated by immunization of radiation-treated tumor cells even with addition of immunoenzyme (Fig.…”

Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer

“…The activities of AdHSV-tk GCV could not only generate signi®cant cytotoxic activities locally and, thereby, contribute to a therapeutic response, but also potentially maximize tumor antigen presentation through its necrotic and apoptotic effects. 1,8,9 The addition of adenoviral vector-delivered locally active IL-12 could potentially maximize the in®ltration of speci®c immune cells and cause them to be activated and mature into active effectors and thus effectively co-operate with AdHSVtk GCV gene therapy. In this study we evaluated the speci®c in®ltration of immune cells within orthotopic mouse prostate cancer under single AdHSV-tk GCV or AdmIL-12 in situ gene therapy and combined treatment conditions.…”