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Chapter 101 Natural Killer Cell–Based Therapies 1579

reactivation in otherwise similar patients. In conclusion, in addition HLA-E, often expressed on cancer cells. One simple explanation for
to HLA matching, donor selection for KIR genes is a promising how CMV influences NK cell function is by the conversion of
strategy to improve outcome after HCT, but benefit may not be seen HLA-E recognition on CMV-exposed NK cells from inhibition
in all settings. While the benefits of NK cells can be realized in AML, through NKG2A to activation through NKG2C as NK cells usually
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the HLA-matched setting, in the autologous setting, and new express one or the other receptor but not both. Recently, Lee et al
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studies in pediatric ALL, 28,29 the benefit of a KIR B/x donor may be and Schlums et al refined our understanding of subsets of NKG2C
lessened when reduced intensity conditioning is used for transplanta- NK cells by precisely defining them by the additional loss of their
tion by unknown mechanisms. adaptor or signaling proteins spleen tyrosine kinase, EAT-2 and
FcεRγ. They refer to these CMV-induced, long-lived cells as “adap-
tive NK cells” drawing parallels between these cells and the T-cell
Making Natural Killer Cells Antigen Specific arms of the (adaptive) immune system. In support of this, CMV
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induced a unique NK-cell methylation signature resembling CD8 T
Despite their ability to recognize malignant transformation or viral cells that was distinctly different from conventional/canonic NK cells.
infection, NK cells are limited by their lack of antigen specificity. In summary, data suggest that CMV exposure, latent CMV, and
Bispecific or Trispecific killer engagers (termed BiKEs or TriKEs) have CMV reactivation has a profound effect on the NK cell repertoire
been developed to overcome this limitation. These novel drugs use with induction of adaptive NK cells. This is important in transplanta-
the single chain antigen binding regions of antibodies (scFv) to tion because 25% to 50% of seropositive patients will reactivate
redirect NK cells to targets. For instance, scFvs directed against CD16 CMV. It has recently been discovered in the post-gancyclovir era that
on NK cells can be combined with an scFv against a tumor-associated CMV reactivation protects against transplant relapse and prolongs
antigen (i.e., CD33). They promote the formation of an immuno- disease-free survival 35,36 suggesting that adaptive NK cells may play a
logic synapse that is both antigen specific and leads to the engagement role as antitumor effectors that merits further study. Recently, IL-12/
of other receptor/ligand pairs between NK cells and their targets. For IL-18 in addition to IL-15 has been shown to induce a population
example, CD16x33 BiKEs have been designed to target AML, and of primed NK cells that are long lived, and these cells are in clinical
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have the additional benefit of recognizing and killing CD33 trials. How these cells compare to CMV-induced adaptive NK cells
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myeloid-derived suppressor cells. The activation induced by BiKEs is under study.
and TriKEs is potent enough to overcome inhibitory signaling
through class I recognizing NK cell receptors. This platform is flexible
and modular (for example, CD19 could be easily substituted for Adoptive Transfer of Natural Killer Cells
CD33), making it an exportable therapeutic approach without the
need for gene therapy. The CD16x19x22 TriKE construct targets two Although methods to exploit the beneficial effects of NK cells
tumor-associated antigens (CD19 and CD22) via CD16, or alterna- engrafting after allo-HCT are increasing, it should be recognized that
tively via the agonistic 41BB-ligand. An alternative approach being NK cells are also well suited for adoptive cellular therapies. Many
explored by some groups is the introduction of CARs into NK cells, groups tested methods to induce autologous NK cell activity, such as
but difficulties in lentiviral gene transduction may make other treatment with prolonged, low-dose IL-2 subcutaneously, higher dose
approaches such as the introduction of CARs into induced pluripo- IL-2 intravenously, and infusions of ex vivo IL-2–activated NK cells.
tent stem cell (iPS)-derived NK cells or NK cell lines a more realistic While these approaches induced in vivo NK cell expansion and
approach because of their off-the-shelf renewal properties. function, they were shown by several investigational teams to have
only limited clinical efficacy; therefore, the Minnesota Group pio-
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neered the use of haploidentical NK cell infusions. This approach
Control of Viral Infection was based on the likelihood that haploidentical NK cells, educated
in the donor, would mediate stronger graft-versus-leukemia reactions
Perhaps the greatest advance in NK cell biology over the past 5 years because they are not exposed to immune suppressive mechanisms
derives from studies of the impact of murine CMV on NK cells. It seen in cancer patients. It was further hypothesized that this would
had been recognized that murine CMV infection leads to expansion result in a higher frequency of alloreactive NK cells (NK cells with
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of a population of Ly49H NK cells that recognize the murine CMV inhibitory receptors functionally educated through a different inhibi-
protein M157. Following repeat challenges with CMV, these cells tory receptor that will not be inhibited by class I expressed by the
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expand and attenuate CMV disease. Moreover, Ly49H cells can be tumor). The safety and success of NK cell infusions was established
adoptively transferred and protect mice from CMV-induced lethality. in a trial using haplotype mismatched, related-donor NK cell prod-
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In 2004, Lopez-Botet and colleagues found a unique population ucts followed by subcutaneous IL-2 to induce in vivo NK survival
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of NKG2C NK cells in CMV-seropositive but not CMV-seronegative and expansion. Successful expansion was achieved only after a
humans. These cells were not induced by other herpes viruses such lymphodepleting regimen of high dose cyclophosphamide and
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as herpes simplex virus or Epstein-Barr virus (EBV). NKG2C NK fludarabine. Interestingly, complete remissions in AML correlated
cells were also enriched in vitro when cultured with human CMV with in vivo NK expansion and higher proportions of circulating (and
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infected fibroblasts. Definitive data now shows that NKG2C and functional) NK cells. The importance of the high-dose chemotherapy
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NKG2C /CD57 NK cells expand in vivo when immunosuppressed regimen delivered before NK cell transfer cannot be overstated.
patients reactivate CMV after solid organ or hematopoietic cell Chemotherapy not only creates space for the NK cells to expand, but
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transplantation. 31,32 These NKG2C NK cells are long-lived and also results in a surge of endogenous IL-15 and IL-7 and transiently
exhibit a high frequency of self-KIR expressing NK cells capable of prevents recipient T cells from rejecting allogeneic NK cells. This
enhanced target cell killing and IFN-γ production compared to NK platform allows in vivo expanded NK cells to partially overcome the
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cells lacking NKG2C. These findings suggest that NKG2C NK cells rules of NK cell education and tolerance, potentially obviating the
represent a unique NK cell population primed by human CMV. need to select specific alloreactive NK cell donors. This assumption
Although Ly49 recognizes murine CMV, it is not clear that NKG2C requires formal clinical testing. Other modifications have shown that
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directly recognizes human CMV. The NKG2C population was also elimination of regulatory T cells with IL-2 diphtheria toxin fusion
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found to expand in victims of a hantavirus outbreak in Sweden and protein can enhance the clinical activity of NK cell infusions. Adop-
a chikungunya virus outbreak in Africa, suggesting that these NK tive transfer of haploidentical NK cells has been tested in other set-
cells may be involved in the response to multiple viral infections. tings. In a pediatric cohort, recovery of functional donor-derived
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However, both of these populations also had prior exposure to CMV, CD56 /CD16 NK cells that lysed K562 targets mediated strong
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so at present it is unclear whether these viruses also induce NKG2C ADCC activity against neuroblastoma and leukemic blasts by day
NK cells or whether they lead to concurrent CMV reactivation. It is +14 after the infusion. The use of NK cell–based therapies to target
interesting that NKG2C/CD94 and NKG2A/CD94 both recognize minimal residual disease is being tested. This preemptive approach is