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may render leukemia cells more susceptible to subsequent chemotherapy.
Clinical trials of SAHA, in addition to standard GVHD prophylaxis, are cur-
rently ongoing. An analysis of 20 patients in one trial demonstrates the
safety of 100 mg given daily throughout the transplant course, with only 4
patients developing grade II GVHD (20%) and all GVHD cases completely
resolving with subsequent steroid therapy
[40]
.
The focus of the aforementioned approaches has been to target and/
or eliminate specific cellular populations, such as APCs. But recent work
indicates it may be necessary to alter the process of antigen presentation
itself. A pioneering study by Hill and colleagues demonstrated that recipi-
ent,
non
hematopoietic APCs, some of which are found in the gastrointes-
tinal stroma, are integral in promoting GVHD
[41]
, a finding corroborated
by other investigators
[42]
. These observations may help explain not only
why the GI tract is a common site of GVHD manifestations, but also why
GVHD in this target organ remains exceptionally difficult to treat. If true
in humans, the discovery of disease-propagating, nonhematopoietic APCs
could have profound therapeutic implications regarding the prevention
and treatment of GVHD. It may become necessary either to eliminate the
nonhematopoietic APCs or to inhibit the process of antigen presentation
more globally, a difficult and dangerous endeavor. The importance of this
nonhematopoietic, antigen-presentation paradigm to clinical transplanta-
tion will probably be an active area of future investigations.
498
Creating platforms for new therapies
Current GVHD prophylaxis relies on the administration of calcineurin
inhibitors together with additional immunosuppressive agents (e.g., myco-
phenolate mofetil). Although these agents suppress GVHD, they also inhibit
the reconstitution of the immune system, leaving patients vulnerable to
infectious complications and long-term immune dysfunction. Recently,
efforts to avoid long-term immunosuppression while still decreasing GVHD
have accelerated, with the intent to create a platform amenable to the addi-
tion of immunologically based anti-tumor therapies. Alemtuzumab and
cyclophosphamide are two agents being used to create such platforms.
Alemtuzumab (aka Campath-1H) is a humanized antibody to CD52, a glyco-
protein found on lymphocytes, macrophages, and some dendritic cells. Given
as part of the conditioning regimen, alemtuzumab profoundly depletes allo-
reactive T cells, leading to low rates of acute and chronic GVHD
[43,44]
. Direct
addition of alemtuzumab to the stem cell source
ex vivo
also yields similarly
low rates of GVHD and nonrelapse mortality
[45]
. Low-dose alemtuzumab,
combined with total-body irradiation (TBI) conditioning and Sirolimus pro-
phylaxis, also obviates the need for myeloablative conditioning. In a small
study of transplantation for severe sickle cell disease, 9 of 10 patients experi-
enced remission of their disease, while all 10 survived without development
of acute or chronic GVHD using alemtuzumab + TBI conditioning
[46]
.
Cyclophosphamide targets rapidly dividing T cells but spares hematopoi-
etic stem cells (HSCs) because of the selective ability of HSCs to detoxify
the intermediary metabolite. High-dose cyclophosphamide alone, on days
+3 and +4 following haploidentical transplantation, has been used in order
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