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

• Published in: Human vaccines & immunotherapeutics 2012-11, Vol.8 (11), p.1714-1721
• Main Authors: Kim, Ha, Sin, Jeong-Im
• Format: Article
• Language: English
• Subjects: Animals; antitumor immunity; cisplatin; Cisplatin - therapeutic use; electroporation; Electroporation - methods; Female; IL-12; Interferon-gamma - metabolism; Interleukin-12 - genetics; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - therapy; Mice; Mice, Inbred BALB C; NK cells; Research Paper
• ISSN: 2164-5515; 2164-554X
• DOI: 10.4161/hv.22346

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.