Immunocytokines based on IL-12 for cancer therapy: Enhancing efficacy and reducing toxicity

Interleukin-12 (IL-12) is one of the most potent antitumor agents, but its clinical use is restricted by its high systemic toxicity. Many recent studies have shown that IL-12 toxicity can be reduced by fusing it to antibodies that target the tumor. These types of fusion molecules, also called immunocytokines (ICKs), allow to concentrate the activity of IL-12 in the tumor microenvironment (TME) while decreasing its systemic levels. The antibodies that have been used to engineer IL-12-based ICKs include those targeting tumor antigens, such as CEA and mesothelin, molecules overexpressed in the TME, such as extra domains of fibronectin and DNA/histone complexes exposed in necrotic areas, and immune checkpoints, such as PD-1 and PD-L1. In general, IL-12-based ICKs have shown an improved efficacy and safety profile compared to IL-12 in many preclinical tumor models, as well as synergistic effects when combined with other immunostimulatory molecules like immune checkpoint inhibitors. This has led to clinical trials in which two ICKs, namely huBC1-IL12 and NHS-IL-12 targeting fibronectin extra domain B and DNA/histone complexes, respectively, have been evaluated. These initial trials have shown a high degree of safety, as well as activation of antitumor immune responses in treated patients.