Engineering cytokines for cancer immunotherapy: a systematic review

Abstract

Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production and function of these cytokines are usually dysregulated during malignant tumor progression. Considering their clinical potential and the early successful use of cytokines in cancer immunotherapy, such as interferon alpha-2b (IFNα-2b; IntronA®) and IL-2 (Proleukin®), cytokine-based therapeutics have been extensively evaluated in many follow-up clinical trials. Following these initial breakthroughs, however, clinical translation of these natural messenger molecules has been greatly limited owing to their high-degree pleiotropic features and complex biological properties in many cell types. These characteristics, coupled with poor pharmacokinetics (a short half-life), have hampered the delivery of cytokines via systemic administration, particularly because of severe dose-limiting toxicities. New engineering approaches have been developed to widen the therapeutic window, prolong pharmacokinetic effects, enhance tumor targeting and reduce adverse effects, thereby improving therapeutic efficacy. In this review, we focus on the recent progress and competitive landscape in cytokine engineering strategies and preclinical/clinical therapeutics for cancer. In addition, aiming to promote engineered cytokine-based cancer immunotherapy, we present a profound discussion about the feasibility of recently developed methods in clinical medicine translation.

A facile approach to preparing personalized cancer vaccines using iron-based metal organic framework

“…IL-12 exhibits multiple immunomodulatory functions, such as inducing the differentiation of Th0 into Th1 lymphocytes, increasing the cytolytic activation of NK cells and cytotoxic T lymphocytes, and promoting the secretion of TNF-α and IFN-γ by T cells, all of which facilitates to transform the immunosuppressive cold tumors into immunologically active hot tumors ( 31 ). TNF-α is predominantly produced by activated antigen-presenting cells and is a powerful tumoricidal cytokine, as its name describes, which induces the apoptotic cell death, stimulates the inflammatory response at the tumor sites and inhibits the tumorigenesis ( 31 ). IFN-γ not only exhibits immunomodulatory functions on innate and adaptive immune response, but also has direct cytotoxic effects on tumor cells ( 31 ).…”

“…TNF-α is predominantly produced by activated antigen-presenting cells and is a powerful tumoricidal cytokine, as its name describes, which induces the apoptotic cell death, stimulates the inflammatory response at the tumor sites and inhibits the tumorigenesis ( 31 ). IFN-γ not only exhibits immunomodulatory functions on innate and adaptive immune response, but also has direct cytotoxic effects on tumor cells ( 31 ). Although these kinds of Th1 cytokines, including IL-12, TNF-α, and IFN-γ, are promising in cancer immunotherapy, their clinical application is associated with short half-life, narrow therapeutic window, severe dose-limiting toxicities, and difficulties in large-scale manufacturing ( 31 ).…”

Applications of Intravital Imaging in Cancer Immunotherapy

“…Cytokine therapy is also an important immunomodulatory therapy [ 107 ]. At present, significant effort has been placed into the study of the anti-tumor therapeutic mechanism of several cytokines, such as IL-2 [ 122 ], IL-12 [ 123 ], IL-15 [ 124 ], IL-24 [ 125 ], IFN-γ [ 126 ], IL-1β [ 127 ], TNF-α [ 128 ], GM-CSF [ 129 ], and others [ 130 ]. For these cytokines, Schumacher’s and Busso’s research groups were the first to show three-dimensional dynamic images of tumor tissues following IFN-γ treatment using in vivo imaging technology [ 131 , 132 ].…”

State-of-the-Art Cancer Immunotherapies

“…Cytokines and exosomes are secreted mediators critical for cell-to-cell communication in the normal and tumor microenvironment. Several cytokines have been shown to exert antitumor activities in many preclinical models, and recent cancer immunotherapy with engineered cytokines targeting tumors with prolonged half-life is more effective [ 4 ]. Exosomes are a new type of extracellular vesicles that modulate the cell signaling pathway in normal and tumor cells via mainly microRNAs (miRNAs) [ 5 ].…”

“…Cytokine-based cancer immunotherapy is still promising, but these cytokine therapies have currently been supplanted by more efficacious therapies such as ICI. Nevertheless, cancer immunotherapy with engineered cytokines, i.e., cytokines combined with other immunotherapies to improve the targeting potential, half-life, and adverse effects, revives the potential of cytokine-based cancer immunotherapy [ 4 ]. Indeed, a novel IL-15-based immunocytokine called GT-00AxIL15, which includes antibodies targeting a tumor-associated glycosylated epitope of MUC1, has recently been developed and effectively delivered to solid tumors with potent antitumor effects [ 21 ].…”