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Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters

Gene Therapy volume 25, pages 93–103 (2018)Cite this article

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Abstract

The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines results in serious, potentially life-threatening, adverse effects. By contrast, nucleic acid transfer via electroporation (EP) is a safe and effective method of delivering plasmid-encoded cytokines to tumors. Intratumoral delivery of IL-12 plasmid DNA by electroporation (IT-pIL12-EP) produced objective response rates in Phase 2 clinical trials in metastatic melanoma. However, only 17.9% of patients receiving IT-pIL12-EP show a complete therapeutic response. Here, we sought to improve the antitumor efficacy of our clinical IT-pIL12-EP plasmid electroporation platform. We evaluated multiple plasmid designs for IL-12 expression. IL-12 expression from a plasmid incorporating a picornavirus-derived co-translational P2A site was the most effective in expressing IL-12p70. In addition, modifying the electroporation parameters improved transfection efficiency and expression of plasmid-derived IL-12p70, as well as its downstream effector IFN-γ in vivo. Finally, using a murine melanoma model that is representative of the intended target patient population, we show that combining modified electroporation conditions with the pIL12-P2A plasmid expression enhances the systemic antitumor response. These improvements to the IT-pIL12-EP platform may improve patient clinical response rates and survival when translated to clinical trials.

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Author information

Authors and Affiliations

  1. Oncosec Medical Inc., 5820 Nancy Ridge Drive, San Diego, CA, 92121, USA

    C. Burkart, A. Mukhopadhyay, S. A. Shirley, J. H. Wright, A. Bahrami & D. A. Canton

  2. Fred Hutchinson Cancer Center, 1100 Fairview Avenue N., Seattle, WA, 98109, USA

    R. J. Connolly, J. S. Campbell & R. H. Pierce

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  1. C. Burkart
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  2. A. Mukhopadhyay
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  9. D. A. Canton
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Correspondence to D. A. Canton.

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All authors are past or present employees of Oncosec Medical Inc. Dr. Canton, Dr. Connolly, Dr. Campbell, Dr. Bahrami, and Dr. Pierce are inventors of patents, pending and published.

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Burkart, C., Mukhopadhyay, A., Shirley, S.A. et al. Improving therapeutic efficacy of IL-12 intratumoral gene electrotransfer through novel plasmid design and modified parameters. Gene Ther 25, 93–103 (2018). https://doi.org/10.1038/s41434-018-0006-y

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  • DOI: https://doi.org/10.1038/s41434-018-0006-y

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