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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    ABSTRACT: A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.
    Full-text · Article · Jun 2013 · BioDrugs
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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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    ABSTRACT: Tumor necrosis factor (TNF) is a cytokine with well known anticancer properties and is being utilized as anticancer agent for the treatment of patients with locally advanced solid tumors. However, TNF role in cancer biology is debated. In fact, in spite of the wealth of evidence supporting its antitumor activity, the cascade of molecular events underlying TNF-mediated tumor regression observed in vivo is still incompletely elucidated. Furthermore, some preclinical findings suggest that TNF may even promote cancer development and progression. With this work we intend to summarize the molecular biology of TNF (with particular regard to its tumor-related activities) and review the experimental and clinical evidence currently available describing the complex and sometime apparently conflicting relationship between this cytokine, cancer biology and antitumor therapy. We also propose a model to explain the dual effect of TNF based on the exposure time and cytokine levels reached within the tumor microenvironment. Finally, we overview recent research findings that might lead to new ways for exploiting the anticancer potential of TNF in the clinical setting.
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