Electrogenetherapy of B16.F10 murine melanoma tumors with an interleukin-28 expressing DNA plasmid

Abstract

Augmented delivery of cytokine-expressing DNA plasmids to subcutaneous tumors has been demonstrated to result in a level of enhanced anti-tumor activity. One delivery enhancement method which has been evaluated is in vivo electroporation (EP), a contact-dependent delivery technique where electric pulses are hypothesized to augment the transfer of DNA into cells and tissues through the induction of temporary cell membrane pores. Previous work by members of our group, as well as others, has demonstrated the anti-tumor effects of DNA plasmids expressing the cytokines IL-12 and IL-15. In this report the potential anti-tumor activity of a relatively newly-described cytokine, IL-28, was measured when administered intratumorally as a DNA expression plasmid (designated pIL28) to established murine (B16.F10) melanoma tumors. The administration of the IL-28 expressing plasmid was performed through enhanced delivery methods. One method was EP and the other a non-contact dependent technique using a helium plasma stream. IL-28 is a member of the type III interferon family of cytokines that has been characterized as possessing potent anti-viral activity. This cytokine has been demonstrated to function as an adjuvant in small animal model vaccination protocols and stimulates CD8+ CTL responses. In addition, stimulation of anti-tumor activity has been demonstrated in several studies using IL-28. Based on these activities, it was hypothesized that this cytokine could, when delivered through a DNA expression plasmid, mediate anti-tumor activity. The results of this study indicated that enhanced delivery of pIL-28 resulted in attenuation of tumor growth, compared with non-enhanced delivery. Of note, this is the first proof-of-concept experiment, of our knowledge, documenting the ability of a non-contact dependent helium plasma-based delivery method to mediate the enhancement of an anti-tumor effect by a cytokine-expressing DNA plasmid. This suggests the use of the helium plasma delivery method as an alternative or adjunctive method to EP for the effective delivery of agents that possess potential anti-tumor activity.

Keywords: :

• interleukin-28
• DNA plasmid
• electroporation
• helium plasma
• B16.F10 murine melanoma
• tumor growth attenuation

Conflict of Interest

Richard Connolly, Mark Jaroszeski and Kenneth Ugen are inventors on patents and patent applications involving the technology utilized in this study. Additionally, Mark Jaroszeski holds stock options in Inovio Pharmaceuticals, Inc., a company whose major emphasis is the development of electrical delivery technologies. None of the other authors of the work declare any conflicts of interest.

Acknowledgments

The studies described in this report were, in part, supported by technology further developed and characterized as part of grant AI079706 from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH. Its contents are solely the responsibility of the authors and do not necessarily represents the official views of NIAID or NIH. We also acknowledge Dr. David Weiner of the University of Pennsylvania for graciously providing the IL-28 expressing plasmid used in this study.