Electrotransfer of IL-15/IL-15Rα Complex for the Treatment of Established Melanoma

SIMPLE SUMMARY: The stimulation of the immune system through the administration of immunomodulatory agents such as cytokines has the potential to be an effective anti-cancer therapy. Obtaining the correct dose is an important aspect with respect to minimizing toxicity and obtaining the desired effect. A method to decrease the toxicity of this type of treatment is to replace the high-dose recombinant protein injections by using DNA expressing genes for one or more of these anti-cancer agents. In this current study, we have evaluated the delivery of interleukin-15 and its receptor in the form of plasmid DNA in a mouse melanoma model. We utilize a delivery approach that can deliver plasmid DNA in a manner that results in the desired level of expression being produced and induces a potent anti-tumor response as well as an immune memory response. ABSTRACT: Gene electrotransfer (GET) is a safe, reliable, and effective method of delivering plasmid DNA (pDNA) to solid tumors. GET has been previously used to deliver interleukin-15 (IL-15) to mouse melanoma, resulting in long-term tumor regression and the survival of a percentage of treated animals after challenge. To enhance this effect, we evaluated modulating the expression levels of IL-15 and co-expressing its receptor, IL-15Rα. GET was used to deliver plasmids encoding IL-15 and IL-15Rα to established B16.F10 tumors on days 0, 4, and 7. Two delivery protocols that yielded different expression profiles were utilized. Mice that were tumor-free for 50 days were then challenged with B16.F10 cells on the opposite flank and monitored for an additional 50 days. The amount of IL-15 expressed and the presence or absence of IL-15Rα in the treated tumors did not significantly affect the tumor regression and long-term survival. Upon challenge, however, low levels of IL-15 were more protective and resulted in a greater production of anti-tumor cytokines such as IFN-γ and MIP-1β and a greater amount of CD11b+ and CD3e+ cells infiltrating tumors. While mice with high levels of IL-15 showed CD11b+ and CD3e+ cell infiltrate, there was a substantial presence of NK cells that was absent in other treated groups. We can conclude that the level of IL-15 expressed in tumors after GET is an important determinant of the therapeutic outcome, a finding that will help us finetune this type of therapy.