期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 70, 期 5, 页码 1305-1321出版社
SPRINGER
DOI: 10.1007/s00262-020-02749-8
关键词
Natural killer cell; Ovarian cancer; Leukemia; N-803; IL-15 superagonist; Cancer immunotherapy
资金
- Ruby and Rose foundation
- Dutch Cancer Society
- Radboud University Medical Center
- Dutch Society for Immunology
- Swedish Foundation for Strategic Research
- Swedish Cancer Foundation
N-803 is a promising IL-15-based compound that enhances HPC-NK cell expansion and functionality both in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could potentially improve cancer immunotherapy.
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 alpha (IL-15R alpha) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15R alpha 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)gamma 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 IFN gamma-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.
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