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

Abstract

Simple SummaryThe 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.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.