Improving TNF as a cancer therapeutic: Tailor-made TNF fusion proteins with conserved antitumor activity and reduced systemic side effects

Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
BioFactors (Impact Factor: 4.59). 07/2009; 35(4):364-72. DOI: 10.1002/biof.50
Source: PubMed


Tumor necrosis factor (TNF) is highly pleiotropic cytokine regulating diverse cellular processes such as proliferation, cell migration, angiogenesis, differentiation, apoptosis, necrosis, but also survival. Because of its name-giving tumor necrosis-inducing capabilities, TNF has attracted attention very early for antitumor therapy. Although TNF is in clinical use for treatment of soft tissue sarcoma in isolated limb perfusion, its broad use in tumor therapy is prevented so far by its strong systemic proinflammatory effects. Nevertheless, over the past decade, a variety of tailor-made TNF variants have been developed with the aim to reduce TNFs systemic activity without losing its antitumoral effects. Here, we review the progress made toward improving the efficacy of TNF by genetic engineering, tumor targeting, and introduction of prodrug concepts.

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    • "Unfortunately, despite the impressive anti-tumor effects observed in animal models, phase I–II clinical trials, carried out few years later, showed that TNF induces toxic effects and no, or very low, anti-tumor responses when administered systemically to patients [21, 22]. Attempts were made, therefore, to prepare less toxic TNF mutants and to increase its efficacy by combining it with other drugs or cytokines or by manipulating its half-life in the circulation [23, 24]. Although these strategies did not meet initial expectations, later studies, reported in the early 1990s, showed that the loco-regional administration of high-dose TNF in combination with chemotherapeutic drugs induces high response rates in patients with melanoma or sarcoma of the extremities [25–28]. "
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    • "Mutants of both insulin and tumor necrosis factor (TNF) have also been developed with enhancement of their therapeutic properties. TNF was re-designed with the intent of improving its deathinducing targeting toward tumors and reducing its systemic side effects (Wajant, et al., 2005; Gerspach, et al., 2009). This attempt is a true challenge with a multifunctional, pleiotropic cytokine such as TNF; nevertheless some progress has been made. "

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