Combined treatment with interleukin-18 and low-dose interleukin-2 induced regression of a murine sarcoma and memory response

Among cytokines applied for immunotherapy of cancer, one of the most successful approaches to date involves systemic delivery of high-dose interleukin (IL)-2. However, the clinical utility of high-dose IL-2 has been limited by significant adverse effects, including vascular leak syndrome. Given this limitation, many attempts to decrease the dosage of IL-2 while maintaining its antitumor therapeutic effects are being made. In this study, the authors observed that combined use of IL-18 and low-dose IL-2 synergistically promoted in vitro proliferation of natural killer cells with up-regulation of IL-2 receptor-α and also synergistically stimulated cytolytic activity and interferon-γ production by these cells. Furthermore, intratumoral injections of these two cytokines completely eradicated day-12 established subcutaneous tumor and induced CD4⁺-dependent memory in a MCA205 murine tumor model. Observed primary antitumor responses depended largely on natural killer cells and partly on CD8⁺ T cells. Fas-L pathway and interferon-γ production were critical in tumor eradication. These results indicate that combined administration of IL-18 and low-dose IL-2 could be a new model for cancer immunotherapy, which probably engages the activation of natural killer cells through interferon-γ- and Fas-L-dependent pathways.