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Sci Transl Med. 2016 Sep 21;8(357):357ra123. doi: 10.1126/scitranslmed.aaf2341.

Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
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.
3
Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZC Leiden, Netherlands.
6
Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. tfehnige@wustl.edu.

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.

PMID:
27655849
PMCID:
PMC5436500
DOI:
10.1126/scitranslmed.aaf2341
[Indexed for MEDLINE]
Free PMC Article

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