IL-15 superagonist N-803 improves IFNγ production and killing of leukemia and ovarian cancer cells by CD34 +  progenitor-derived NK cells.

Autor: Van der Meer JMR; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Maas RJA; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Guldevall K; Department of Applied Physics, Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Klarenaar K; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., de Jonge PKJD; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Evert JSH; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.; Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands., van der Waart AB; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Cany J; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Safrit JT; NantKwest, Culver City, CA, USA., Lee JH; ImmunityBio, Culver City, CA, USA., Wagena E; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands., Friedl P; Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.; David H. Koch Center for Applied Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Cancer Genomics Center, Utrecht, The Netherlands., Önfelt B; Department of Applied Physics, Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden., Massuger LF; Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands., Schaap NPM; Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands., Jansen JH; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Hobo W; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Dolstra H; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. harry.dolstra@radboudumc.nl.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2021 May; Vol. 70 (5), pp. 1305-1321. Date of Electronic Publication: 2020 Nov 03.
DOI: 10.1007/s00262-020-02749-8
Abstrakt: Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion,  N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.
Databáze: MEDLINE
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