A Checkpoint for Systemic Toxicity

Abstract

Cytokines such as interleukin 12 (IL-12) possess myriads of functions in the modulation of immune responses but despite having significant therapeutic potential they can also stimulate toxic activation of immune cells. In a study by Mansurov and colleagues, the pleiotropic effects of IL-12 were successfully prevented by attaching the cytokine to a genetically engineered fragment of IL-12 receptor and allowing the complex to be processed by tumor-associated proteases. Subsequently, when injected into cancer-containing mice, IL-12 was only activated in the tumor microenvironment. Upon administration, systemic toxicity was not observed while the masked IL-12 was able to stimulate immune cells and the tumors responded to immune checkpoint therapy. This methodology could be suitable to curate more cytokines as therapeutic agents for multiple pathologies that are related to immunological demodulations without having systematic toxicity. Nat. Biomed. Eng. 10.1038/s41551-022-00888-0 (2022).