title: Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.
abstract: Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Romee
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Berrien-Elliott
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Wagner
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brea A
authors.initials: BA
authors.lastname: Jewell
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schappe
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Abdel-Latif
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Schneider
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Willey
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Carly C
authors.initials: CC
authors.lastname: Neal
authors.affiliation: Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Liyang
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yi-Shan
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZC Leiden, Netherlands.
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZC Leiden, Netherlands.
authors.forename: Frans
authors.initials: F
authors.lastname: Claas
authors.affiliation: Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. tfehnige@wustl.edu.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D019264:Adoptive Transfer; D000368:Aged; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008297:Male; D051379:Mice; D008875:Middle Aged; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D012074:Remission Induction; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D008024:Ligands; D055607:Receptors, Natural Killer Cell