Improving TNF as a cancer therapeutic: tailor-made TNF fusion proteins with conserved antitumor activity and reduced systemic side effects.
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.
Gerspach
Jeannette
J
Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany. jeanette.gerspach@izi.uni-stuttgart.de
Pfizenmaier
Klaus
K
Wajant
Harald
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D053222:Fas Ligand Protein / Q000138:chemical synthesis; D005818:Genetic Engineering; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use; D048069:Tumor Necrosis Factors / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C464840:tumor Necrosis Factor-alpha, CNGRC fusion protein, mouse; C464839:tumor necrosis factor-alpha, CNGRC fusion protein, human