Intratumoral Delivery of Interleukin 12 Expression Plasmids withIn VivoElectroporation Is Effective for Colon and Renal Cancer

Abstract

We report on an antitumor treatment involving electrogene therapy (EGT), a newly developed in vivo gene transfer method using electroporation. We carried out in vivo EGT in a subcutaneous model of CT26 colon carcinoma cells, using plasmid DNAs encoding interleukin 12 (IL-12) subunits. For this purpose, we developed two IL-12 expression systems: a cotransfer system using a plasmid encoding the IL-12 p40 subunit and a plasmid encoding the IL-12 p35 subunit, and a single-vector system using a plasmid expressing a p40-p35 fusion protein. Both transfer systems significantly inhibited the growth of CT26 tumor. Immunohistochemical analysis of IL-12 EGT-treated tumors revealed enhanced infiltration of CD8(+) cells into the tumor tissue, while reverse transcriptase-polymerase chain reaction confirmed the increased expression of interferon gamma within treated tumors. The same IL-12 EGT applied to the nude mouse model was not effective, suggesting the critical role of T cell infiltration in this treatment. The inhibitory effects revealed in experiments in which previously treated mice were rechallenged with a second inoculation of CT26 tumor cells suggested that IL-12 EGT may also establish partial systemic antitumor immunity. The growth of IL-12 EGT-treated Renca tumors, a renal cell carcinoma, was also significantly inhibited. These findings suggest that EGT of the IL-12 gene has the potential to be an effective anticancer gene therapy.

Cancer Electrogene Therapy with Interleukin-12

“…The antitumor effectiveness of intratumoral IL-12 electrogene therapy was demonstrated also in other types of cancer, such as colon carcinoma, renal cancer, lymphoma, breast carcinoma and sarcoma mouse tumor models [75][76][77][78][79][80]. Treatment of CT26 colon carcinoma tumors with 3 times repeated intratumoral IL-12 electrogene therapy resulted in significant inhibition of tumor growth.…”

Gene Therapy Progress and Prospects: Nonviral vectors

“…IL-12 was also employed for electroporation after intratumor injection. 11 Our laboratory recently reported the use of a syringe electrode, with which same transfection efficiency could be achieved by using much lower electric field strength than that of conventional electrode. Tissue damage by the electric field is thus minimized.…”

Visualization of in vivo electroporation-mediated transgene expression in experimental tumors by optical and magnetic resonance imaging

“…Many earlier studies have shown that intratumoral gene delivery by in vivo EP strongly inhibits tumor growth and generates systemic immunity against tumor in experimental models. [11][12][13][14][15] Furthermore, a clinical trial for melanoma treatment using in vivo EP has been started. 6 Like other gene delivery methods, non-invasive monitoring of in vivo EP-mediated transgene expression of the introduced gene is a critical issue for optimizing the protocol and ensuring efficacy of the treatment.…”