Biology Reference
In-Depth Information
be “alloreactive” toward cells expressing only “foreign” MHC class I mole-
cules. In both preclinical and clinical analyses, transplants containing allo-
reactive NK cells decreased relapse and increased survival, particularly for
myeloid malignancies
[62]
. Results for KIR-mismatched transplants have
not been uniform, however, which could relate to differences in the dis-
eases treated, patient selection, conditioning regimens, or stem cell sources
[63,64]
. Dramatic results with KIR mismatching have been observed in hap-
loidentical settings when T cells were removed from the donor graft (e.g.,
through rigorous selection of CD34
+
cells), but further trials are required.
Purified NK cells may also be infused preemptively as a stand-alone therapy
[65,66]
. Ten patients who received KIR-mismatched NK cells after treatment
for AML showed donor NK cell engraftment without evidence of GVHD and
100% survival at 2 years. Several groups are currently evaluating the optimal
integration of NK cell therapy into allogeneic transplantation and future
progress will probably result from increased understanding of basic NK cell
biology.
Maintenance therapy following allogeneic
transplantation
501
Relapse following allogeneic transplantation very often occurs within the
first 6 months. During this time, immune reconstitution is incomplete and
there are large gaps in the immunosurveillance against tumor cells. Post-
transplant maintenance therapy could theoretically prevent relapse, but
such therapy must not impair the function of newly engrafted cells. One
maintenance agent that possesses known efficacy for relapsed BCR-ABL
+
chronic myelogenous leukemia (CML) is imatinib. Given as maintenance
therapy within the first month after transplant, imatinib maintained a
major, molecular remission in 17 of 22 at-risk CML patients
[67]
. Second-
generation tyrosine kinase inhibitors are also being tested in a similar
manner and in some centers have already become the standard of care for
BMT patients with Ph
+
disease.
The DNA-hypomethylating agent azacitidine is another candidate for
maintenance therapy. Administration of azacitidine was well tolerated after
BMT and produced a median 1-year event-free survival of 58% in patients
with high-risk MDS or AML
[68]
. A randomized trial comparing azacitidine
maintenance therapy to supportive care is ongoing. Other novel anti-tumor
agents, such as the proteasome inhibitor bortezomib or the NEDD8-acti-
vating enzyme inhibitor MLN4924, are also being explored in this context.
Improved anti-leukemia effects through T-cell
manipulation
Infusion of a large number of tumor-reactive CTLs should theoretically
prevent relapse, and many investigators have explored the antileukemic
potential of T-cell infusion. But the logistics of this effort remain daunting,
particularly given the great risks of iatrogenic GVHD. To avoid this compli-
cation, one strategy transduces a “suicide gene” into polyclonal populations
of T cells, which are then infused into patients. If GVHD develops, a prodrug
Search WWH ::
Custom Search