Immunotherapy of murine prostate cancer using whole tumor cells killed ex vivo by herpes simplex viral thymidine kinase/ganciclovir suicide gene therapy.
Whole cell cancer vaccines are currently under clinical evaluation. Their immunogenicity may depend on the mode of death of the vaccine cells prior to uptake by professional antigen-presenting cells and crosspriming of T cells. Destruction of tumor in vivo by genetic prodrug activation therapy leads to a marked local and systemic immune response, local T-cell infiltration and the establishment of T-cell memory. We postulated that this immunostimulation may be due to induction of danger signals and the inherent immunogenicity of products of HSVtk/ganciclovir kill. Using established models of murine prostate cancer, we have evaluated the efficacy of anti-tumor vaccines comprising irradiated allogeneic or autologous whole cells expressing HSVtK, which are first killed in vitro by prodrug activation using ganciclovir. HSVtk/ganciclovir-induced cell kill was through the induction of apoptosis. The vaccine was found to be effective in both models and superior to traditional irradiated whole tumor cells even after single doses. Protection against tumor challenge was associated with marked proliferative and Th1 cytokine responses. This approach would be applicable clinically in terms of ease of vaccine production, safety, storage and avoidance of potential toxicities of in vivo gene transfer.
Pandha
Hardev
H
Department of Oncology, St George's Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK. hpandha@sghms.ac.uk
Eaton
Jonathan
J
Greenhalgh
Rebecca
R
Soars
Diane
D
Dalgleish
Angus
A
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015774:Ganciclovir / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy; D008297:Male; D011471:Prostatic Neoplasms / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D018139:Simplexvirus / Q000201:enzymology; D018417:Th1 Cells / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics*; D014764:Viral Proteins / Q000235:genetics
D019496:Cancer Vaccines; D016207:Cytokines; D014764:Viral Proteins; D013937:Thymidine Kinase; D015774:Ganciclovir