Spatiotemporally programming cytokine immunotherapies through protein engineering

Cytokines have long been considered promising cancer immunotherapy agents due to their endogenous role in activating and proliferating lymphocytes. However, since the initial FDA approvals of Interleukin-2 (IL-2) and Interferon-alpha (IFNalpha) for oncology over 30 years ago, cytokines have achieved little success in the clinic due to narrow therapeutic windows and dose-limiting toxicities. This is attributable to the discrepancy between the localized, regulated manner in which cytokines are deployed endogenously versus the systemic, untargeted administration used to date in most exogenous cytokine therapies. Furthermore, cytokines' ability to stimulate multiple cell types, often with paradoxical effects, may present significant challenges for their translation into effective therapies. Recently, protein engineering has emerged as a tool to address the shortcomings of first-generation cytokine therapies. In this perspective, we contextualize cytokine engineering strategies such as partial agonism, conditional activation and intratumoral retention through the lens of spatiotemporal regulation. By controlling the time, place, specificity, and duration of cytokine signaling, protein engineering can allow exogenous cytokine therapies to more closely approach their endogenous exposure profile, ultimately moving us closer to unlocking their full therapeutic potential.

Automated summary

Cytokines have shown potential as cancer immunotherapy, but their clinical success has been limited due to narrow therapeutic windows and dose-limiting toxicities. The systemic administration used in most exogenous cytokine therapies does not mimic the localized, regulated deployment of endogenous cytokines. Furthermore, cytokines' ability to stimulate multiple cell types with paradoxical effects poses challenges for their translation into effective therapies. Protein engineering offers strategies to address these limitations and bring exogenous cytokine therapies closer to their endogenous exposure profile, unlocking their full therapeutic potential.