Research ArticleCancer

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

Science Translational Medicine  21 Sep 2016:
Vol. 8, Issue 357, pp. 357ra123
DOI: 10.1126/scitranslmed.aaf2341

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Natural killers of leukemia

Natural killer cells, part of the innate immune system, play a role in immune responses against exogenous pathogens as well as cancer. Recent studies have identified the existence of memory-like characteristics in some natural killer cells, and Romee et al. investigated these memory cells’ potential as a cancer therapy. The authors compared human natural killer memory cells to non-memory control cells, then demonstrated their effectiveness against myeloid leukemia models in vitro and in mice. They also performed a clinical trial in human patients with acute myeloid leukemia, where the natural killer memory-like cells again demonstrated antileukemia effects, some of which produced clinical remissions.

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.

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