Immunocytokines with activity-on-demand by combination with small molecule inhibitors

Abstract

Dose-limiting systemic toxicity constitutes a major impediment to the application of cytokines in cancer therapy. To enhance the therapeutic index, tumor-directed antibody-cytokine fusion proteins, i.e., immunocytokines, are developed for targeting-mediated cytokine enrichment at the tumor site, allowing for an effective local concentration at a lower dosage. However, the therapeutic window is narrow, making strategy improvements to further reduce off-target toxicity of great interest. Recently, the combination with a small molecule inhibitor of the cytokine signaling pathway has been proposed to suppress systemic toxicity during the delivery stage of the immunocytokine without interfering with its therapeutic efficacy. In this issue of EMBO Molecular Medicine , proof of concept is provided by Rotta et al in preclinical studies on tumor-targeted IL-12 in combination with a JAK inhibitor.