Page 1774 - Hematology_ Basic Principles and Practice ( PDFDrive )

1578 Part IX Cell-Based Therapies

and may also have a role in preventing graft-versus-host disease has been demonstrated in pediatric, but not adult ALL, suggesting
(GVHD). that unique interactions between NK cells and targets might account
for these differences.

CLINICAL APPLICATIONS OF NATURAL KILLER CELLS Natural Killer Cell Function After Hematopoietic
Cell Transplantation
Determination of Donor Natural Killer
Cell Alloreactivity Despite their high numbers early after HCT, engrafting NK cells are
not fully functional. This has been demonstrated by several investiga-
It is widely accepted that the ability of NK cells to contribute to tors. 19,20 Foley et al studied simultaneous NK cell functions in
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protection from relapse and infection requires that they be function- response to target cell exposure. They reported that degranulation
ally competent and present in sufficient numbers. As described earlier, stimulated by class I–negative targets recovered early after transplant,
NK cells are alloreactive against targets that lack self-HLA ligands for suggesting that NK cells could be educated through either NKG2A
the inhibitory receptors that contributed to their education or licens- or KIR. NK cells from double umbilical cord grafts exhibited CD107a
ing. Recent studies have suggested that the diversity of the NK cell hyperfunction compared to adult unrelated donors, which may
repertoire is massive (6000–30,000 phenotypically distinct individual explain the enhanced relapse protection seen in this setting. In
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clones in an individual), allowing NK cell education to occur marked contrast, IFN-γ production was severely diminished for at
through multiple receptor–ligand interactions. Several models have least 6 months post-HCT, especially in settings of T-cell depleted
been developed to predict NK cell alloreactivity, but the aforemen- grafts (even without posttransplant immune suppression) or grafts
tioned diversity suggests that the in vivo response is more complicated containing naive T cells (UCB), suggesting that NK cells require T
than the existing models. Donor and recipient HLA typing can be cells for optimal education. This defect could be rapidly reversed by
used to determine KIR–ligand mismatch or incompatibility, as short-term exposure to IL-15. In addition, and in contrast to CD107a
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defined by the Perugia group, which predicts that donor-derived degranulation, IFN-γ production could only be educated through
NK cells will be alloreactive in the graft-versus-host direction when self-KIR (NK cells expressing KIR that encounter their cognate
recipients lack C2, C1, or Bw4 alleles that are present in the donor. ligand [MHC class I] in the recipient), suggesting a hierarchy of
Alternatively, in the KIR–ligand absence model, alloreactive potential thresholds for different NK effector functions. Lastly, different con-
is based entirely on the number of KIR ligands (HLA molecules) a ditioning regimens may have varied effects on the tempo of NK and
recipient lacks. The receptor–ligand model of alloreactivity requires T-cell reconstitution after transplantation and may therefore affect
knowledge of the inhibitory KIR expression in the donor (based on function and impact on clinical outcomes.
assessment of the donor KIR genotype or phenotype). Because KIR
genes have multiple alleles with variable levels of expression and
functional activity, alloreactivity may be best determined by evaluat- Donor Selection Based on Killer
ing the donor KIR genotype with functional assessments of their KIR Immunoglobulin-Like Receptor Genotype
phenotype.
Another approach to capitalize on the beneficial effects of NK cells
The Role of Natural Killer Cells in Hematopoietic after HCT is to consider the full KIR genotype of potential donors.
In a study of 448 patients undergoing myeloablative HLA-matched
Cell Transplantation or -mismatched unrelated donor (URD) HCT for AML, the 3-year
overall survival was significantly higher after transplantation from a
NK cells are the first lymphocyte population to reconstitute after KIR B/x genotype donor (containing at least 1 B haplotype), irrespec-
HCT. Engrafted alloreactive NK cells may mediate: (1) decreased tive of recipient KIR genotype, with a 30% improvement in relative
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rates of GVHD by targeting of host APC; (2) improved engraftment risk of relapse-free survival. A subsequent analysis of 1409 URD
by secretion of stem cell trophic cytokines and elimination of host transplant recipients confirmed these findings and refined the benefi-
immune barriers; (3) targeting minimal residual leukemia and reduce cial effect of KIR B genes to AML patients. Similar effects were not
relapse; and (4) decreased infectious complications. An early report seen in ALL. In addition, this later study showed that the most benefit
published by the Perugia Group in 2002 demonstrated a beneficial from donor KIR B genotype was localized to genes present in the
effect of alloreactive NK cells and showed that donor KIR–ligand centromeric part of the KIR locus. The greatest protection from
mismatched NK cells in the GVHD direction play a key role in relapse and best disease-free survival, in both HLA matched and
achieving durable remission after CD34+ selected (T-cell deplete) mismatched transplants, was associated with donors homozygous for
haploidentical transplantation for AML, but not ALL. KIR–ligand this region. Donors could be stratified by KIR into those with Best
mismatched donors were associated with improved engraftment, (Cen-B homozygous present in 11% of the population), Better (≥2
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decreased relapse, and decreased GVHD. However, in a long-term B defining domains as seen in 20% of the population), or Neutral
follow up of 112 patients, only decreased relapse in patients trans- donor KIR genotypes. A publicly available calculator to determine
planted while in complete remission and improved disease-free sur- this stratification is available online (http://www.ebi.ac.uk/ipd/kir/
vival were maintained. Subsequent analyses of the role of KIR–ligand donor_b_content.html). KIR genotyping as few as three of the best
mismatching and KIR–ligand absence in different settings have HLA matched donor candidates should substantially increase the
produced mixed results. In umbilical cord blood (UCB) transplanta- frequency of URD transplants from donors with favorable KIR gene
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tion, the effect of KIR–ligand mismatching on outcomes appears to content (from 31% to 79%) AML. New studies suggest that the
depend on either the intensity of the preparative regimen or the drugs benefit of Better/Best donors is further enhanced in HLA-C1 but not
+
used (i.e., ATG or not). 16,17 In a 2009 study of 169 children treated HLA-C2 recipients, which may inhibit KIR2DS1 NK cells by
with autologous HCT for neuroblastoma, KIR–ligand absence was downtuning NK cell educations in the context of HLA-C2. 24,25
strongly associated with improved survival and decreased risk of Several prospective trials using different graft sources designed to
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disease progression. Inconsistent effects of KIR–ligand mismatch select donors for relapse protection are underway. The benefit of
and KIR–ligand absence strategies are likely caused by differences in donor KIR B/x has been verified in other studies, and all KIR B genes
the stem cell source, conditioning, degree of T-cell depletion, and contribute the clinical benefit. The B-haplotype KIR genes 2DL5A,
post-HCT immunosuppression used, all of which can affect NK cell 2DS1, and 3DS1 were associated with an AML-specific fourfold
development, education, and function. Despite this confusion, NK reduction in relapse in a study of 246 T-cell depleted HLA-matched
cell effects continue to emerge, implicating them as having a key role sibling transplants, and KIR B haplotypes were associated with
in protecting against relapse in myeloid malignancies. Similar promise improved survival and reduced TRM in association with less CMV