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EMBO Mol Med. 2020 Jan 8:e11223. doi: 10.15252/emmm.201911223. [Epub ahead of print]

Safe eradication of large established tumors using neovasculature-targeted tumor necrosis factor-based therapies.

Author information

1
Cytokine Receptor Laboratory, VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
2
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium.
3
Orionis Biosciences, Boston, MA, USA.
4
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
5
CNRS UMR 5235, University of Montpellier, Montpellier, France.
6
VIB Center for Medical Biotechnology, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

Abstract

Systemic toxicities have severely limited the clinical application of tumor necrosis factor (TNF) as an anticancer agent. Activity-on-Target cytokines (AcTakines) are a novel class of immunocytokines with improved therapeutic index. A TNF-based AcTakine targeted to CD13 enables selective activation of the tumor neovasculature without any detectable toxicity in vivo. Upregulation of adhesion markers supports enhanced T-cell infiltration leading to control or elimination of solid tumors by, respectively, CAR T cells or a combination therapy with CD8-targeted type I interferon AcTakine. Co-treatment with a CD13-targeted type II interferon AcTakine leads to very rapid destruction of the tumor neovasculature and complete regression of large, established tumors. As no tumor markers are needed, safe and efficacious elimination of a broad range of tumor types becomes feasible.

KEYWORDS:

cancer; interferons; neovasculature; targeted therapy; tumor necrosis factor

PMID:
31912630
DOI:
10.15252/emmm.201911223
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