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C H A P T E R 101

NATURAL KILLER CELL–BASED THERAPIES

Sarah Cooley, Michael R. Verneris, and Jeffrey S. Miller

INTRODUCTION
and IL-21. IL-15 is of particular importance for NK cell development
The antitumor effect of allogeneic hematopoietic cell transplanta- and homeostasis. Trans presentation of IL-15 by IL-15Rα on APCs
tion (allo-HCT) is mediated through both high-dose chemotherapy appears to be the physiologic source of cytokine leading to NK
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and immune reactions. Although relapse rates remain high, reduced activation. These cytokines enhance the expression of CD56 on
intensity regimens do provide protection from relapse, demonstrating activated cells, producing a population that should not be confused
that allogeneic immune cells can eradicate leukemia and lymphoma. with steady-state CD56 bright cells, which have different functional
Exactly which cell populations contribute to the graft-versus-leukemia properties.
effect is not entirely established, and may vary among individuals and
diseases. Immune cell populations can be mechanistically divided
into two broad categories; the innate (natural killer [NK] cells and Natural Killer Cell Functions
antigen presenting cells [APC]) and adaptive (T cell and B cells)
arms of the immune system. It is commonly believed that mature NK cells provide a link between the innate and adaptive immune
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innate immune cells are able to perform their biologic functions systems and play an important role in immune surveillance, preg-
without prior activation, while in contrast adaptive immune cells nancy outcomes, and response to infections (see Fig. 101.1). NK cell
require antigen presentation, activation, and expansion before they function can be divided into several separate activities that include
can act. These paradigms are changing. It is becoming increasingly interaction with APCs, activation, expansion, homing to malignant
clear that human cytomegalovirus (CMV) induces profound changes or virally infected targets, direct cell–cell killing, and cytokine pro-
in the NK-cell repertoire promoting NK-cell populations that are duction. These responses may differ based on the stimulus and the
capable of immunologic memory. These populations have been NK cell subset studied. Activated NK cells produce cytokines and
termed “adaptive NK cells.” Likewise, under certain conditions, T chemokines, including IFN-γ, tumor necrosis factor, granulocyte
cells can mediate major histocompatibility complex (MHC)-unre- macrophage colony-stimulating factor, and transforming growth
stricted killing, typically considered a quality of the innate system. factor beta. NK cells also express β2 integrins such as leukocyte
Importantly, cells from all components of the immune system are function–associated antigen-1 (LFA-1) and CD2, which bind to
regulated in concert to achieve a balance between immune response molecules such as intracellular adhesion molecule-1 and LFA-3 on
and tolerance. Because the antitumor efficacy of conventional APCs and other cells. If the balance of activating and inhibitor
cytotoxic agents is limited by off target toxicity and resistance, receptor signaling favors activation (see later), target-cell apoptosis
targeted immune cell–based therapies provide an attractive alterna- occurs via membrane bound death receptors (Fas ligand [FasL] and
tive. Progress in cytokine biology and improvements in techniques tumor necrosis factor-related apoptosis inducing ligand [TRAIL]) or
to separate, expand, and target cells through immune engagers or by releasing cytotoxic molecules (perforin and granzyme) into a small
chimeric antigen receptors (CARs) have transformed the concept area between the NK cell and the target cells (called the immune
of NK cell–based therapy. This chapter examines characteristics synapse). These activated NK cells then produce cytokines. It is
of NK cells and discusses how they may be manipulated to treat believed that the activating signal threshold required for IFN-γ pro-
malignancy and combat infection, both in HCT and non-HCT duction is higher than that needed for CD107a degranulation or
settings. cytotoxicity after target cell exposure. It is not known whether
cytokine production or direct cell killing is physiologically most
important for a therapeutic NK cell response, and it is likely that
NATURAL KILLER CELL BIOLOGY both are required for efficacy.
NK cells were first described functionally in 1975 for their ability
to lyse virally infected cells and tumor targets without prior sensi- Natural Killer Cell Receptors
tization. NK cells comprise 10% to 15% of the peripheral blood
(PB) lymphocyte pool in normal humans, but they are also found Unlike T cells or B cells that express a single, unique, rearranged
in the bone marrow, spleen, liver, lymph nodes, lungs, and preg- antigen receptor, NK cells express a variety of different receptors that
nant uterus (Fig. 101.1). Defined by the expression of CD56 or trigger either inhibition or activation. Many of the inhibitory recep-
NKp46 and by the lack of a CD3/T-cell receptor complex, they tors are MHC class I–specific, such that engagement of self results in
develop from marrow-derived progenitors via distinct developmen- a reduction in NK cell function. Thus recognition of MHC class I,
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tal stages in secondary lymphoid tissue. Mature NK cells can be which is ubiquitously expressed by healthy tissues, leads to NK cell
dim
functionally distinguished by CD56 density. The CD56 subset tolerance. In contrast, the loss of MHC class I, which occurs during
exhibits natural cytotoxicity (killing of class I–negative targets) the process of viral infection and malignant transformation, leads to
and displays Fc receptors (CD16) that facilitate the recognition of the lack of engagement of these inhibitory receptors and, in turn,
immunoglobulin-coated targets, a process called antibody-dependent permits activation of the NK cell via other receptor–ligand interac-
dim
cellular cytotoxicity (ADCC). CD56 cells also produce cytokines tions. The activating receptors often recognize ligands that are
in response to the above stimuli. In contrast, CD56 bright NK cells are induced by cell stress, such as MHC I–related chain A and B, the
more proliferative and are less cytotoxic. CD56 bright cells respond to unique long (UL) 16-binding proteins (ULBPs), nectin-2, and
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monocyte-derived cytokines (interleukin [IL]-12, IL-15, and IL-18) CD48. The net balance of activating and inhibitory signals deter-
to rapidly produce large amounts of interferon gamma (IFN-γ). NK mines the NK cell response to a target, favoring elimination of
cells also proliferate and become activated in response to IL-2, IL-15, infected, transformed, or stressed cells.
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