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mouse NK cells can be detected in the lymph nodes. A pivotal study dem-
onstrated that NK cells can play critical roles in viral infections by limiting
T-cell responses
[57]
. These data suggest that while direct anti-tumor effects
can occur when using activated NK cells in cancer therapy, care must be
exercised, as these same cells can also impair and suppress T-cell responses
that may be necessary for long-term efficacy.
NK cells in humans
The first trials in humans to harness the anti-tumor properties of NK cells
focused on the use of IL-2 to activate autologous NK cells both
ex vivo
and
in vivo. Ex vivo
IL-2-stimulated autologous peripheral blood mononuclear
cells (PBMCs) were infused into patients with melanoma, lymphoma, and
renal cell carcinoma with additional high-dose IL-2. NK cell cytotoxicity was
observed in these patients; however, these treatments were unsuccessful.
Furthermore, high-dose IL-2 infusions to stimulate NK cells
in vivo
were also
clinically disappointing and were associated with high toxicities. As a conse-
quence, various studies looked at the efficacy of low-dose IL-2 infusions for
a wide range of malignancies, including AML, lymphoma, and breast can-
cer
[58,59]
. Ultimately, infusion of IL-2 or adoptive transfer of IL-2-activated
autologous NK cells failed for two main reasons: competition with the recip-
ient's lymphocytes for cytokines and “space” and because autologous NK
cells were inhibited by self-HLA class I. As inhibitory KIRs and their ligands
were further characterized, the next approach to utilizing NK cells as immu-
notherapy focused on allogeneic NK cells. These NK cells would be alloreac-
tive against a target that lacked the ligand for their inhibitory receptors.
338
Allogeneic NK cells with the potential to mediate anti-tumor effects can
be delivered in the context of an HSCT or adoptively transferred follow-
ing
ex vivo
stimulation. The efficacy of the first approach was highlighted
in a 2002 study from the Perugia University group
[51]
, who provided evi-
dence that donor alloreactive NK cells decreased graft rejection, enhanced
engraftment, and mediated the graft-versus-leukemia (GVL) effect in the
absence of GVHD following mismatched HSCT. The potential for NK allo-
reactivity in the GVH direction was determined using what would become
known as the KIR ligand incompatibility or KIR ligand mismatch model.
For example the donor expresses all three ligands for the inhibitory KIR (C1,
C2, and Bw4), whereas the recipient expresses only C2 and Bw4; therefore
it is predicted that the donor will have C1-specific alloreactive NK cells that
will not be inhibited in the recipient and can potentiate the GVL effect. This
model assumes that the donor expresses the inhibitory KIRs that recognize
each self-HLA ligand. Of the 92 AML and acute lymphocytic leukemia (ALL)
patients who received HLA-mismatched grafts, 34 patients were KIR ligand
incompatible in the GVH direction. Transplanted donor alloreactive NK
cells protected against graft rejection, GVHD, and AML relapse. Without NK
cell mismatch, the probability of event-free survival at 5 years was 5%, and
with an NK cell mismatch the probability was 65%. This occurred only in
patients with AML; there were no beneficial effects seen for patients with
ALL, speculated to be due to the lack of the adhesion molecule, LFA-1, on
the surface of ALL blasts
[60]
. Donor alloreactive NK clones could also be
identified in the recipient up to 12 months after transplant. Using mouse
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