Expanded clinical‐grade membrane‐bound IL‐21/4‐1BBL NK cell products exhibit activity against acute myeloid leukemia in vivo

• Published in: European journal of immunology Vol. 50; no. 9; pp. 1374 - 1385
• Main Authors: Zhao, Xiang‐Yu, Jiang, Qian, Jiang, Hao, Hu, Li‐Juan, Zhao, Ting, Yu, Xing‐Xing, Huang, Xiao‐Jun
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.09.2020
• Subjects: 4-1BB Ligand - immunology; 4-1BB Ligand - metabolism; 4‐1BBL; Acute myeloid leukemia; Adult; Aged; Animals; Female; Humans; IL‐21; Immunodeficiency; Immunotherapy; Interleukins - immunology; Interleukins - metabolism; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - transplantation; Leukemia; Leukemia, Myeloid, Acute - therapy; Leukocytes (mononuclear); Male; Mice; Middle Aged; Minimal residual disease; Myeloid leukemia; Natural killer cells; NK cells; Patients; Peripheral blood mononuclear cells; Spleen; Tumor necrosis factor; Xenograft Model Antitumor Assays; Xenografts; Minimal residual disease; 4-1BBL; NK cells; Acute myeloid leukemia; IL-21
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201948375

Background Adoptive NK cell infusion is a promising immunotherapy for acute myeloid leukemia (AML) patients. The aim of this study was to test the activity of clinical‐grade membrane‐bound IL‐21/4‐1BBL‐expanded NK cell products against AML in vivo. Methods Fresh peripheral blood mononuclear cells (PBMCs) were incubated with equal numbers of irradiated membrane‐bound IL‐21/4‐1BBL‐expressing K562 cells for 2–3 weeks to induce clinical‐grade NK cell expansion. Results Expansion for 2 and 3 weeks produced ∼4 and 8 × 109 NK cells from 2 × 107 PBMCs. The production of CD107a and TNF‐α in NK cell products in response to AML cell lines and primary blasts was higher than that observed in resting NK cells. The 2‐week expanded NK cell products were xenografted into immunodeficient mice with leukemia and were persistently found in the BM, spleen, liver, lung, and peripheral blood for at least 13 days; furthermore, these expanded products reduced the AML burden in vivo. Compared with matched AML patients with persistent or relapsed minimal residual disease (MRD+) who underwent regular consolidation therapy, MRD+ patients who underwent NK treatment had better overall survival and showed no major adverse events. Conclusions Clinical‐grade mbIL‐21/4‐1BBL‐expanded NK cells exhibited antileukemic activity against AML in vitro and in vivo. Clinical‐grade NK cell products were produced with irradiated membrane‐bound IL‐21/4‐1BBL‐expressing K562 cells. NK cell products showed enhanced expression of activating receptors and chemokine receptors, therefore exhibit cytotoxicity against acute myeloid leukemia cells in vitro, in leukemia mice model as well as in persistent minimal residual disease positive leukemia patients .