Biology Reference
In-Depth Information
and educated in the donor. The first trial of this approach was conducted
at the University of Minnesota
[95]
. Forty-three patients with metastatic
melanoma, metastatic renal cell carcinoma, Hodgkin's disease, or poor
prognosis AML were enrolled in the trial. PBMCs were collected from hap-
loidentical related donors and CD3 depleted before being incubated over-
night in IL-2. Prior to NK cell infusion, patients underwent a preparative
regimen that involved three different chemotherapy preparations: high
cyclophosphamide and fludarabine (Hi-Cy/Flu), low cyclophosphamide
and methylprednisone, or fludarabine. Following infusion patients received
IL-2 daily for 14 days. NK cell expansion was observed only for patients
receiving the preparatory regimen of Hi-Cy/Flu. Successful expansion of
NK cells was determined by the detection of greater than 100 NK cells/μl
of blood 12-14 days after infusion. On this protocol 30% of poor progno-
sis AML patients achieved a complete remission, whereas no beneficial
effects were observed for the other diseases. However, this remission was
not durable and patients ultimately relapsed. Since NK cells expanded only
following high-dose preparative regimens, the addition of 400 cGy of total
body irradiation was proposed to further deplete host immune cells and
create space for donor NK cells to expand. This addition also meant that
patients needed to be “rescued” with a CD34
+
selected stem cell infusion.
On this protocol NK cell expansion was much more successful and 75% of
patients achieved measurable NK cell expansion. Furthermore leukemia
clearance was observed in 66% of patients. No acute GVHD was observed,
though death due to infection was common (46%). It should also be noted
that, while there was induction of remission, ultimately this therapy did
not result in lasting remissions. Additionally there was no influence of KIR-
ligand incompatibilities.
344
The use of adoptive transfer of NK cells to treat various malignancies has
resulted in mixed results. Shi and colleagues
[96]
infused haploidentical
KIR-mismatched NK cells into 10 patients with relapsed multiple myeloma
followed 14 days later with an autologous stem cell graft. Five patients
achieved near complete remission. Bachanova and colleagues
[97]
treated 6
patients with non-Hodgkin's lymphoma with infusion of haploidentical NK
cells and found that NK cells expanded poorly
in vivo
and host T regulatory
cells were significantly increased after NK cell infusion and IL-2 administra-
tion. Similarly, adoptively transferred NK cells failed to expand in patients
with breast and ovarian cancers and a similar increase in host T regulatory
cells was also observed
[98]
.
Expanding NK cells
In the initial report describing the clinical efficacy of adoptively transfer-
ring NK cells, PBMCs were CD3 depleted and IL-2 activated overnight. After
infusion IL-2 was added daily for 14 days to expand these donor NK cells
in vivo.
Current platforms used also involve the depletion of CD19 cells.
Strategies to enhance NK cell expansion both
in vivo
and
ex vivo
have been
undertaken. The addition of IL-2 is necessary to expand NK cells
in vivo;
however, IL-2 also activates T regulatory cells, which can suppress NK
cell proliferation and NK cell cytotoxicity
[99]
. In an experimental tumor
model using pretreatment with Ontak (denileukin diftitox) to deplete host
Search WWH ::
Custom Search