To reduce systemic side effects of alpha interferon but retain immune cell stimulating activity, Cauwels et al. constructed a mutated cytokine with >100x lower potency targeted to Clec9A+ cross-presenting dendritic cells (Clec9A-mAFN). In vivo, peri-tumoral Clec9A-mAFN stimulated Clec9A+ DCs in tumor-draining lymph nodes, controlled tumor growth in multiple models as well as full strength interferon but without toxicity, and synergized with other therapies, including checkpoint blockade. Activity depended on Batf3+ DCs and CD8+ T cells.

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 interferon (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 1000-fold more potent on target cells, allowing specific signaling in selected cell types only. Type I IFN-derived AcTaferon-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 AcTaferons provide a novel class of highly efficient, safe, and broad-spectrum off-the-shelf cancer immunotherapeutics with no need for a tumor marker.

Author Info: (1) Ghent University and VIB. (2) Ghent University and VIB. (3) University Montpellier. (4) University Montpellier. (5) Ghent University and VIB. (6) Molecular Biotechnology, Ghent

Author Info: (1) Ghent University and VIB. (2) Ghent University and VIB. (3) University Montpellier. (4) University Montpellier. (5) Ghent University and VIB. (6) Molecular Biotechnology, Ghent University and VIB. (7) Orionis Biosciences. (8) Ghent University and VIB. (9) Ghent University and VIB. (10) University Montpellier. (11) Ghent University and VIB. (12) Ghent University and VIB. (13) Ghent University and VIB. (14) GE06, Ghent University Hospital. (15) Orionis Biosciences. (16) UMR 5235, CNRS. (17) Center for Medical Biotechnology, Cytokine Receptor Laboratory, VIB and Ghent University Jan.Tavernier@vib-ugent.be.

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