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1192 Part IX: Lymphocytes and Plasma Cells Chapter 77: Functions of Natural Killer Cells 1193

is mostly mediated by secretion of soluble factors. NK cells, consti- NATURAL KILLER CELL THERAPY
tutively or upon activation, produce several lymphokines, some with
mostly inhibitory effects on hematopoiesis, such as TNF and IFN-γ, and TO TREAT CANCER
some with mostly stimulatory effects, such as GM-CSF. 36,58 The effector
role of NK cells in rejection of parental marrow graft in irradiated F1 TARGETING NK CELL RECEPTORS
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mice and in suppressing erythropoiesis and phagocytopoiesis in mice Data showing recipients of KIR-incompatible donors have reduced
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infected with lymphocytic choriomeningitis virus (LCMV) demon- relapse of acute myelogenous leukemia (AML) following mismatched
strate that in vivo activated NK cells can affect both allogeneic and syn- allogeneic stem cell transplantation remain the most compelling evi-
geneic hematopoietic progenitor cells. Because of the ability of NK cells dence to support the antitumor activity of NK cells. Further, studies in
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to kill transformed hematopoietic cells, NK cells have been postulated mice showing Ly49-incompatible NK cells mediate graft-versus-tumor
to play an important role in the graft-versus-leukemia reaction in allo- effects have led to clinical trials exploring adoptively infused allogeneic
geneic marrow transplantation but only a modest, if any, role in graft- NK cells in patients with cancer. In humans, pilot studies have shown
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versus-host disease. In haploidentical or mismatched hematopoietic that adoptive transfer of IL-2-activated MHC-mismatched allogeneic
transplantation, the presence on donor NK cells of the KIR not recog- NK cells can proliferate in vivo and can induce tumor regression in
nizing inhibiting ligands on host hematopoietic and malignant cells patients with AML and solid tumors. 69
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results in protection from leukemia relapse. A reduced incidence of A strategy to disrupt inhibitory KIRs to enhance NK tumor kill-
graft-versus-host disease has also been observed and thought to result ing involves blocking KIRs with monoclonal antibodies or genetically
from the elimination of recipient antigen-presenting cells by donor silencing their expression. IPH2101 is a fully human IgG antibody that
4
NK cells. 62 binds to KIR2D, thus blocking its ability to suppress NK cell function.
Studies in a mouse model showing that IPH2101 enhances NK-cell kill-
ing of KIR ligand-matched tumor cells has led to phase I studies eval-
PATHOLOGIC ALTERATIONS IN uating the efficacy of IPH2101-mediated KIR2D blockade in patients
with AML and other hematologic disorders. Genetic disruption of the
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NATURAL KILLER CELL NUMBER inhibitory receptor NKG2A has been shown to enhance NK cell killing
AND FUNCTIONS of HLA-E–expressing tumors ex vivo and in vivo following their infu-
sion into tumor-bearing mice.
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NK cell function and NK cell numbers are often decreased in patho-
logic conditions, including cancer and AIDS. 63,64 The reduced activity ADOPTIVE NATURAL KILLER CELL TRANSFER
or number of NK cells may contribute to disease pathology by decreas-
ing the innate resistance against tumor growth and metastasis in can- Recently, methods have been developed to expand large numbers of
cer patients or against opportunistic infections in AIDS patients. NK human NK cells ex vivo, which provides the opportunity to study the
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cell (and cytotoxic T-cell) hyporesponsiveness is observed in patients efficacy of adoptive NK-cell immunotherapy in patients with cancer.
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with Chédiak-Higashi syndrome, a rare autosomal recessive disease Most expansion cultures utilize irradiated feeder cells such as Epstein-
associated with cellular dysfunction, including fusion of cytoplasmic Barr virus–transformed lymphoblastoid cell lines or the human ery-
granules and defective degranulation of neutrophil lysosomes. NK cell thromyeloblastoid leukemia cell line K562 cells genetically modified
numbers are normal in these patients, but the NK cells present a single, to express membrane bound 4–1BB ligand, IL-15, or IL-21. Expanded
large granule in the cytoplasm and have a severely reduced ability to NK cells have increased surface expression of NK activating receptors
mediate cytotoxicity. 65 and cytotoxicity effector molecules. Compared to resting NK cells,
Malignant acute expansion of NK cells is rare, more frequent expanded NK cells express higher amounts of IFN-γ, Fas ligand, and
in Asians than in whites, and often associated with Epstein-Barr TRAIL, and have markedly enhanced cytotoxicity against K562 and
virus infection. Extranodal NK cell lymphomas occur in both the other tumor cells compared to resting or short-term IL-2–activated NK
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+
nasopharyngeal region and in nonnasal areas as an NK cell (CD2 , cells. Phase I trials of infusing large numbers of these ex vivo expanded
+
–
–
–
CD3 , CD56 , CD16 , CD57 ) leukemia or lymphoma that mostly autologous NK cells are now ongoing in patients with a variety of dif-
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affects extranodal tissues. It affects predominantly men in their fifth ferent cancers. 73
decade and usually has an extremely aggressive clinical course. Aggres- Studies suggest that lenalidomide, an immunomodulatory drug
sive NK cell leukemia is a catastrophic disease that affects young adults derived from thalidomide, and several monoclonal antibodies blocking
and is characterized by the systemic presence of neoplastic NK cells in immune checkpoints, such as anti–PD-1, anti–PD-L1, and anti–CTLA-
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blood and marrow. An entity previously known as “blastic NK cell 4, augment NK-cell–mediated ADCC. 74,75 The advances in our ability
+
lymphoma,” characterized by CD4 , CD56 cells with dermal tropism, to expand NK cells ex vivo now makes it feasible to combine these and
+
is now recognized to represent an expansion of plasmacytoid dendritic other monoclonal antibodies with adoptive NK cell transfer to poten-
cells rather than NK cells. A chronic monoclonal proliferative dis- tially augment their antitumor effects.
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order of LGL with a clinical course that is often relatively indolent is
more commonly observed. Most patients have lymphocytic infiltra- OVERCOMING DEFICIENT NATURAL KILLER
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tion of the marrow. Severe neutropenia and anemia often are observed.
Associated diseases, most commonly rheumatoid arthritis, hepatitis, CELL HOMING
or cancer, are present in up to half of patients. Although cells from Expanded NK cells are inefficient at homing to the marrow and lymph
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all these patients are characterized by a LGL morphology, in approxi- nodes where hematologic malignancies reside. A variety of techniques
mately two-thirds of the cases they represent a monoclonal expansion to improve NK cell homing to these target organs have been described.
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of CD8 T cells, and in only less than one-third of cases they have the NK cell trogocytosis (the transfer of plasma membrane fragments
+
–
typical phenotype and genotype of CD3 , CD56 , CD57 , and, in some from the presenting cell to the lymphocyte) of the membrane-bound
+
+
patients, CD16 NK cells. 68 chemokine receptor CCR7 expressed on K562 cells can be used to
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