Preclinical Development Effective Melanoma Immunotherapy with Interleukin-2 Delivered by a Novel Polymeric Nanoparticle

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-dose injections, resulting in severe side effects. Although adenovirus-mediated IL-2 gene therapy has shown antitumor efficacy, the host antibody response to adenoviral particles and potential biosafety concerns still obstruct its clinical applications. Here we report a novel nanopolymer for IL-2 delivery, consisting of low molecular weight polyethylenimine (600Da) linked by b-cyclodextrin and conjugated with folate (namedH1). H1 was mixed with IL-2 plasmid to form H1/pIL-2 polyplexes of around 100 nm in diameter. Peritumoral injection of these polyplexes suppressed the tumor growth and prolonged the survival of C57/BL6 mice bearing B16–F1 melanoma grafts. Importantly, the antitumor effects of H1/pIL-2 (50 mg DNA) were similar to those of recombinant adenoviruses expressing IL-2 (rAdv-IL-2; 2 10 pfu). Furthermore, we showed that H1/pIL-2 stimulated the activation and proliferation of CD8þ, CD4þ T cell, and natural killer cells in peripheral blood and increased the infiltration of CD8þ, CD4þ Tcells, and natural killer cells into the tumor environment. In conclusion, these results show that H1/pIL-2 is an effective and safe melanoma therapeutic with an efficacy comparable to that of rAdv-IL-2. This treatment represents an alternative gene therapy strategy for melanoma. Mol Cancer Ther; 10(6); 1082–92. 2011 AACR.