An Effective Interleukin-2 Cancer Immunotherapy Delivered by a Novel Polymeric nanoparticle in Melanoma

Abstract

Interleukin-2 (IL-2) has been shown to possess antitumor activity in numerous preclinical and clinical studies. However, the short half-life of recombinant IL-2 protein in serum requires repeated high doses administration, resulting in severe side effects. Although adenovirus-mediated hIL-2 gene therapy has shown antitumor efficacy, the host antibody response to adenoviral particles and potential biosafety misgivings prevented its clinical application. Here we report a novel polymer, consisting of low-molecular weight Polyethylenimine (PEI 600 Da) linked by Cyclodextrin and conjugated with Folate (referred to as H1). The H1 assembled hIL- 2 plasmid to form H1/phIL-2 polyplexes with size around 100 nm. Peritumoral injection of these polyplexes suppressed the tumor growth and prolonged the survival in C57/BL 6 mice bearing B16- F1 cells. Importantly, the antitumor effects of H1/hIL-2 plasmid (DNA 50 mg) were similar to those of Adv-hIL-2 (2 108 pfu). Furthermore, we showed that this treatment activated immune cells such as cytotoxic T lymphocyte and natural killer cells. Interestingly, it has no effect on the number of CD4+CD25+ Treg cells of peripheral blood, which was reported to suppress antitumor immune responses. In conclusion, these results showed that H1/ phIL-2 polyplexes are an effective and safe therapy with an efficacy comparable to that of Adv-hIL-2. This treatment represents an alternative gene therapy strategy for melanoma.