Delivering Type I Interferon to Dendritic Cells Empowers Tumor Eradication and Immune Combination Treatments
| Autor: | Stefaan De Koker, Yann Bordat, Thomas Wueest, Sandra Van Lint, Dominiek Catteeuw, Gilles Uzé, José Van der Heyden, Annick Verhee, Alexander Van Parys, Anje Cauwels, Geneviève Garcin, Niko Kley, Jan Tavernier, Franciane Paul, Bart Vandekerckhove, Elke Rogge, Sarah Gerlo |
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| Přispěvatelé: | Universiteit Gent = Ghent University [Belgium] (UGENT), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Melanoma Experimental [SDV.CAN]Life Sciences [q-bio]/Cancer Apoptosis Mice 03 medical and health sciences 0302 clinical medicine Immune system Cancer immunotherapy Interferon Tumor Cells Cultured medicine Animals Cell Proliferation Mice Inbred BALB C business.industry Melanoma Mammary Neoplasms Experimental Cancer [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy Dendritic Cells Immunotherapy medicine.disease Combined Modality Therapy Immune checkpoint 3. Good health Mice Inbred C57BL 030104 developmental biology Oncology 030220 oncology & carcinogenesis Interferon Type I Immunology Cytokines Female Tumor necrosis factor alpha business medicine.drug |
| Zdroj: | Cancer Research Cancer Research, American Association for Cancer Research, 2018, 78 (2), pp.463-474. ⟨10.1158/0008-5472.CAN-17-1980⟩ |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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