title: Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.
abstract: Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.
authors.affiliation: Department of Microbiology, School of Medicine, Kangwon National University; Chuncheon, Gangwon-do, Korea.
authors.forename: Ha
authors.initials: H
authors.lastname: Kim
authors.forename: Jeong-Im
authors.initials: JI
authors.lastname: Sin
mesh_terms: D000818:Animals; D002945:Cisplatin / Q000627:therapeutic use*; D018274:Electroporation / Q000379:methods*; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma; D002945:Cisplatin