title: Combined HSV-TK/GCV and secondary lymphoid tissue chemokine gene therapy inhibits tumor growth and elicits potent antitumor CTL response in tumor-bearing mice.
abstract: Suicide gene therapy in combination with pro-drugs represents an attractive approach to the treatment of cancer. Unfortunately this approach is limited by difficulty in targeting all tumor cells, especially those at the distant metastases associated with the most complex tumors. For this reason, attempts to stimulate global anti-tumor immune responses at the sites of effective suicide gene/pro-drug-mediated tumor cell destruction are appealing. Here we show that, by including a gene coding for secreted secondary lymphoid tissue chemokine (SLC) along with the herpes simplex virus thymide kinase (HSV-TK) gene in a bicistronic vector for anti-tumor gene therapy in conjunction with the pro-drug ganciclovir (GCV), we are able to mediate a greatly enhanced anti-tumor effect in the murine B16 melanoma tumor model. The data presented suggests that this enhanced antitumor effect is the result of a strong induced CTL immune response resulting from the recruitment of immune cells to the site of HSV-TK/GCV-induced tumor destruction by the potent chemokine SLC.
authors.affiliation: Oncology Research Institute, Greenville Hospital System, SC 29605, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Warren
authors.forename: Wendy
authors.initials: W
authors.lastname: Song
authors.forename: Eric
authors.initials: E
authors.lastname: Holle
authors.forename: Lilia
authors.initials: L
authors.lastname: Holmes
authors.forename: Yangzhang
authors.initials: Y
authors.lastname: Wei
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Wagner
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics* / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D013937:Thymidine Kinase; D015774:Ganciclovir