Spatiotemporally programming cytokine immunotherapies through protein engineering

Abstract

SummaryCytokines 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‐ɑ (IFNɑ) 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.

Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity

“…Antibody-targeted cytokines have been pursued for many years with modest impact, driven in part by the focus on targeting cancer cells lacking truly disease-specific antigens and the problem that their biodistribution is often governed by the cognate cytokine receptor and not the antibody target( 5 , 34 ). Recent approaches, focusing on targeting immune cells through lineage markers or phenotype have shown promising preclinical data( 21 , 35 ).…”

“…Over the last 20 years, protein engineering has emerged as a tool to address the shortcomings of native cytokine therapies( 5 – 7 ). One strategy to increase both safety and efficacy is to engineer cytokines for local delivery and retention within tumors and/or tumor-draining lymph nodes (TDLNs).…”

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs

“…As a result, there have been attempts to combine these therapies with agonistic, or immune-stimulating, agents to overcome tumor resistance mechanisms and drive more durable responses 87,88 . Cytokines, such as IL-2 and IL-12, are one class of agonistic therapies that have shown great promise against human cancers, but suffer from unacceptable toxicities due to their activation of immune cells throughout the body 15,16 . Approaches to restrict the activity of potent cytokines to the tumor have gained momentum, one of which includes the retention of engineered cytokines to tumor extracellular matrix following intratumoral injection 25,[35][36][37] .…”

“…The clinical promise of IL-2 and IL-12 cytokines has been limited by the toxicities observed at therapeutically effective doses 9,10,15,16,59,60 . As such, evaluating if the collagen-anchoring approach would ameliorate cytokine-driven toxicities at doses capable of promoting anti-tumor responses in pet dogs was paramount and translationally relevant.…”

“…As key signaling molecules between immune cells, endogenous immune-stimulating cytokines like IL-2 and IL-12 exhibit tightly controlled spatial distributions and diffusional kinetics to prevent aberrant and pathologic activation. However, in the therapeutic setting, systemically-dosed cytokines can elicit on-target, off-tumor activation of immune cells and subsequently possess an extremely narrow therapeutic window constrained by dose-limiting toxicities [14][15][16] . These clinical limitations resulting from cytokines administered systemically have driven recent interest in protein engineering strategies to mitigate systemic toxicities, through tumor-targeting immunocytokines [17][18][19][20][21] , conditionally-active/masked cytokines [22][23][24][25][26] , and receptor-biased cytokine agonists [27][28][29][30] to enable their inclusivity alongside checkpoint inhibitors and other first-line cancer treatments such as radiation, chemotherapy, and surgery.…”