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Cancer Res. 2018 Jan 15;78(2):463-474. doi: 10.1158/0008-5472.CAN-17-1980. Epub 2017 Nov 29.

Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments.

Author information

1
Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
2
CNRS UMR 5235, University Montpellier, Montpellier, France.
3
Orionis Biosciences, Boston, Massachusetts.
4
Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Gent, Belgium.
5
Cytokine Receptor Laboratory, Flanders Institute of Biotechnology, VIB-UGent Center for Medical Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. jan.tavernier@vib-ugent.be.

Abstract

An ideal generic cancer immunotherapy should mobilize the immune system to destroy tumor cells without harming healthy cells and remain active in case of recurrence. Furthermore, it should preferably not rely on tumor-specific surface markers, as these are only available in a limited set of malignancies. Despite approval for treatment of various cancers, clinical application of cytokines is still impeded by their multiple toxic side effects. Type I IFN has a long history in the treatment of cancer, but its multifaceted activity pattern and complex side effects prevent its clinical use. Here we develop AcTakines (Activity-on-Target cytokines), optimized (mutated) immunocytokines that are up to 1,000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon (AFN)-targeting Clec9A+ dendritic cells (DC) displayed strong antitumor activity in murine melanoma, breast carcinoma, and lymphoma models and against human lymphoma in humanized mice without any detectable toxic side effects. Combined with immune checkpoint blockade, chemotherapy, or low-dose TNF, complete tumor regression and long-lasting tumor immunity were observed, still without adverse effects. Our findings indicate that DC-targeted AFNs provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.Significance: Targeted type I interferon elicits powerful antitumor efficacy, similar to wild-type IFN, but without any toxic side effects. Cancer Res; 78(2); 463-74. ©2017 AACR.

PMID:
29187401
DOI:
10.1158/0008-5472.CAN-17-1980
[Indexed for MEDLINE]
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