Targeted Cytokine Delivery for Cancer Treatment: Engineering and Biological Effects

Abstract

Anti-tumor properties of several cytokines have already been investigated in multiple experiments and clinical trials. However, those studies evidenced substantial toxicities, even at low cytokine doses, and the lack of tumor specificity. These factors significantly limit clinical applications. Due to their high specificity and affinity, tumor-specific monoclonal antibodies or their antigen-binding fragments are capable of delivering fused cytokines to tumors and, therefore, of decreasing the number and severity of side effects, as well as of enhancing the therapeutic index. The present review surveys the actual antibody–cytokine fusion protein (immunocytokine) formats, their targets, mechanisms of action, and anti-tumor and other biological effects. Special attention is paid to the formats designed to prevent the off-target cytokine–receptor interactions, potentially inducing side effects. Here, we describe preclinical and clinical data and the efficacy of the antibody-mediated cytokine delivery approach, either as a single therapy or in combination with other agents.

The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

“…IL-2 and IL-12) or compounds (i.e. sunitinib) have in fact been shown to lead to increased concentrations of the drugs within the tumors, reduced severity of the side effects, and enhanced therapy efficacy ( 163 – 167 ). In the future, it is conceivable that similar approaches may be exploited also for the delivery of ICIs.…”

Revitalizing Cytokine‐Based Cancer Immunotherapy through Advanced Delivery Systems

“…[21,22,23] Another method, so-called immunocytokine, is done by fusing the cytokine with the targeting moiety of an antibody, thus arming the cytokine with the capability to increase the retention at tumor sites. [24] For both strategies, many modified cytokines, including IL-2, IL-12, and IL-15, have entered clinical investigations. [21,25] Nonetheless, modification of the cytokine protein structure can lead to alterations of the biological potency and could require dose compensation.…”

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

“…Targeting efficacy was shown to be determined not only by the antibody but also significantly influenced by the particular cytokine, with potential implications for off-target toxicity (Hutmacher and Neri, 2019 ). Most advanced in clinical trials are immunocytokines with the cytokines IL-2, TNF, and IL-12 (Rybchenko et al, 2023 ). These pro-inflammatory cytokines are vasoactive and can induce further cytokine production, potentially causing adverse events such as hypotension, nausea, vomiting, flu-like symptoms, and, in some cases liver function abnormalities (Rudman et al, 2011 ; Johannsen et al, 2010 ).…”