Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 345

The role of NK cells in viral therapy

Another potential therapeutic approach to eliminating tumors is the use
of oncolytic viruses. An oncolytic virus is a virus that preferentially infects,
replicates in, and lyses malignant cells. In most instances, the virus is
engineered to increase tumor specificity. The first report of an engineered
oncolytic virus described the ability of a thymidine kinase-negative mutant
herpes simplex virus-1 (HSV-1) that was attenuated for neurovirulence
to treat gliomas [129] . The virus was able to lyse human glioma cell lines
in vitro and inhibit the growth of human glioma in nude mice and pro-
longed survival. While NK cells have anti-tumor properties, which have
been discussed, NK cells also have potent antiviral properties. In fact,
individuals with NK cell deficiencies are particularly susceptible to viral
infections [130] . As NK cells are critical components of the host response
to viral infections they may be both beneficial and a hindrance when using
oncolytic viruses as a cancer therapy. For effective use of oncolytic viruses,
they must be able to enter the cell, infect, and replicate before the immune
response targets the virus. HSV-1- and vaccinia virus-infected cells, com-
monly used as oncolytic viruses, can be rapidly lysed by NK cells, prevent-
ing virus dissemination and thereby potentially preventing the efficacy
of these oncolytic viruses [131] . Upon activation NK cells will also recruit
other innate immune cells such as monocytes and dendritic cells and cells
of the adaptive immune response, T cells and B cells, that may further
impede the efficacy of the virus. To counteract the host's antiviral immune
response the addition of chemotherapy to suppress the immune system
coupled with oncolytic viruses may increase the potential for this line of
therapy [132] . Alternative approaches involve harnessing the potent antivi-
ral properties of NK cells. This may involve viruses that upregulate ligands
for NK-cell-activating receptors and downregulate ligands for the inhibi-
tory receptor, e.g., HLA class I. Bergmann and colleagues [133] engineered
influenza A virus to be used as a potential oncolytic virus. NKp46 expressed
by all NK cells recognizes influenza A hemagglutinin on infected cells.
This engineered virus was used to infect prostate cancer cells in vitro, and
infected cells were eliminated by NKp46-mediated target cell lysis [134] .
NKp46 activation was also shown to overcome MHC class I inhibition. An
alternative approach may involve immune suppression to ensure total
viral infection of the tumors, particularly in metastatic tumors, followed
by adoptive transfer of activated NK cells that will be able to eradicate the
infected tumor cells.

349

Another virus, CMV, may also play a role in eliminating malignant cells. A
member of the Herpesviridae family, CMV causes asymptomatic or mild
illness in healthy individuals; however, for patients immunosuppressed by
HIV infection or solid organ or hematopoietic cell transplantation, CMV is
a potentially life-threatening complication [135] . CMV remains latent in the
host, and latent CMV reservoirs have been found in cells of the myeloid lin-
eage and in endothelial cells [135] . Recently CMV reactivation after HSCT
has been shown to be beneficial. Elmaagacli and colleagues [136] reported
that early CMV reactivation is associated with a reduced risk of relapse in
AML patients undergoing allogeneic HSCT from HLA-matched siblings or
unrelated donors. All transplants were unmanipulated. The risk of leukemic