Abstract
Electroporation (EP)-assisted intralesional delivery of Interleukin-2 (IL-2) plasmid (pDNA) has the potential to increase the local concentration of the expressed cytokine for an extended time in the injected tumors while minimizing its systemic concentration, in comparison with systemic delivery of the recombinant cytokine. Nonclinical Investigational New Drug application-enabling studies were performed in mice to evaluate the effect of intratumoral administration of murine IL-2 pDNA on local expression and systemic distribution of IL-2 transgene as well as the inhibition of established tumor growth. The safety of repeated administrations of a human IL-2 pDNA product candidate with EP was evaluated in rats. Following the nonclinical safety and efficacy studies, a human IL-2 pDNA product candidate intralesionally administered with EP to metastatic melanoma patients is currently being investigated in a phase I clinical trial.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
1. Hanna, E., Zhang, X., Woodlis, J., Breau, R., Suen, J., and Li, S. (2001) Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site. Cancer Gene Ther. 8, 151–157.
2. Li, H., Cao, M.Y., Lee, Y., et al. (2005) Virulizin, a novel immunotherapy agent, activates NK cells through induction of IL-12 expression in macrophages. Cancer Immunol. Immunother. 54, 1115–1126.
3. Lucas, M.L. and Heller, R. (2003) IL-12 gene therapy using an electrically mediated nonviral approach reduces metastatic growth of melanoma. DNA Cell Biol. 22, 755–763.
4. Tomura, T., Nishi, T., Goto, T., et al. (2001) Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer. Hum. Gene Ther. 12, 1265–1176.
5. Torrero, M.N., Henk, W.G., and Li, S. (2006) Regression of high-grade malignancy in mice by bleomycin and interleukin-12 electrochemogenetherapy. Clin. Cancer Res. 12, 257–263.
6. Kishida, T., Asada, H., Satoh, E., et al. (2001) In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice. Gene Ther. 8, 1234–1240.
7. Yamashita, Y., Shimada, M., Hasegawa, H., et al. (2001) Electroporation-medicated Interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res. 61, 1005–1012.
8. Li, S., Zhang, X., Xia, X., et al. (2001) Intramuscular electroporation delivery of IFN-alpha gene therapy for inhibition of tumor growth located at a distant site. Gene Ther. 8, 400–407.
9. Lohr, F., Lo, D.Y., Zaharoff, D.A., et al. (2001) Effective tumor therapy with plasmid-encoded cytokines combined with in vivo electroporation. Cancer Res. 61, 3281–3284.
10. Matsubara, H., Gunji, Y., Maeda, T., et al. (2001) Electroporation-mediated transfer of cytokine genes into human esophageal tumors produces anti-tumor effects in mice. Anticancer Res. 21, 2501–2504.
11. Chi, C.H., Wang, Y.S., Lai, Y.S., and Chi, K.H. (2002) Anti-tumor effect of in vivo IL-2 and GM-CSF electrogene therapy in murine hepatoma model. Anticancer Res. 22, 3153–3322.
12. Lucas, M.L., Heller, L., Coppola, D., and Heller, R. (2002) IL-12 plasmid delivery in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol. Ther. 5, 668–675.
13. Hartikka, J., Sawdey, M., Cornefert-Jensen, F., et al. (1996) An improved plasmid DNA expression vector for direct injection into skeletal muscle. Hum. Gene Ther. 7, 1205–1217.
Grossblatt, N. (ed.) (1996) The guide for the care and use of laboratory animals, 7th edn. National Academies Press, Washington, DC.
15. Tomayko, M.M. and Reynolds, C.P. (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother. Pharmacol. 24, 148–154.
16. Horton, H.M., Planchon, R.R., Sawdey, M., et al. (2007) Therapy of primary and metastatic murine tumors by intratumoral administration of interleukin-2 plasmid DNA with electroporation. Cancer Therapy 5, 125–132.
17. Draize, J.H. (1959) Appraisal of the safety of chemicals in food, drugs and cosmetics. The Association of Food and Drug Officials of the United States, Austin, TX, pp. 49.
18. Parker, S.E., Vahlsing, H.L., Lew, D., et al. (1999) Cancer gene therapy using plasmid DNA—pharmacokinetics and safety evaluation of an IL-2 plasmid DNA expression vector in rodents and nonhuman primates. Biopharm. Appl. Technol. Biopharm. Dev. 12, 18–24.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Humana Press
About this protocol
Cite this protocol
Horton, H.M., Lalor, P.A., Rolland, A.P. (2008). IL-2 Plasmid Electroporation: From Preclinical Studies to Phase I Clinical Trial. In: Li, S. (eds) Electroporation Protocols. Methods in Molecular Biology™, vol 423. Humana Press. https://doi.org/10.1007/978-1-59745-194-9_28
Download citation
DOI: https://doi.org/10.1007/978-1-59745-194-9_28
Publisher Name: Humana Press
Print ISBN: 978-1-58829-877-5
Online ISBN: 978-1-59745-194-9
eBook Packages: Springer Protocols