Biology Reference
In-Depth Information
Enhancement of GVL /GVT
Another approach to improving the outcome of ASCT focuses on improv-
ing efficacy, namely enhancing the GVL/GVT effect of transplantation.
This has predominantly been through two main mechanisms: adoptive
T-cell therapy and vaccine therapies post-transplantation ( Table 14.2 ).
DLI is one of the best examples of adoptive T-cell therapy, and attempts to
preserve GVL/GVT while minimizing GVHD following DLI have included
selection of particular immune cell subsets, the nonselective expansion of
activated cells, or the infusion of cells that target particular antigen speci-
ficities [137-139] . Advances in the generation of chimeric antigen recep-
tor T cells against tumor antigens have the potential to enhance adoptive
T-cell therapy post-transplantation [140,141] . The adoptive transfer of T
cells had been a preferred approach over implementation of an anti-tumor
vaccine post-transplantation, given the relatively lymphopenic environ-
ment that exists in this setting. However, the post-transplantation setting
may also be optimal for these vaccine approaches as the donor immune
system has not yet become tolerized to the host tumor [111] . Furthermore,
the patterns of tumor antigens that are immunogenic differ from patient to
patient and the use of whole tumor cell-based vaccines allows for an indi-
vidualized approach toward immunization [115] . In mice, whole tumor cell-
based vaccination after immune reconstitution following transplantation
resulted in improved survival after challenge with live tumor cell infusion,
with decreased tumor burden and increased numbers of IFN-γ-positive T
cells compared with nonvaccinated mice [142] . In humans, vaccination of
post-ASCT acute myeloid leukemia patients with an autologous granulo-
cyte/macrophage colony-stimulating factor (GM-CSF)-secreting vaccine
resulted in an improved 2-year survival over historical controls [143] . The
use of immune adjuvants, such as GM-CSF, TLR agonists, or CD40 ligand,
helps to overcome the relative immune suppression that defines the early
post-transplant period [111] .
316
Separation of GVL /GVT from cGVHD
Lastly, to improve the outcome and efficacy of ASCT and to make it a via-
ble therapeutic option for more patients, attempts are ongoing to separate
GVL/GVT from aGVHD and cGVHD. Some of these approaches have been
mentioned previously and include global or selective T-cell depletion or
T-cell manipulation of the donor stem cell graft, the induction of mixed chi-
merism with delayed DLI, and manipulation of the cytokine environment
to favor a specific type of immune response ( Table 14.3 ).
Exhaustive T-cell depletion of the stem cell graft decreases cGVHD but at
the cost of increased disease relapse and thus decreased GVL/GVT. Selec-
tive removal of certain T-cell subsets has been attempted, as distinct T-cell
subsets appear to contribute to GVHD and GVL/GVT differently. Ex vivo
CD8 T-cell depletion decreased rates of GVHD while preserving the GVL/
GVT effect of ASCT at the expense, though, of increased graft rejection
[144,145] . This high rate of nonengraftment may be overcome with added
immunosuppression or higher doses of CD34 cells but is currently hin-
dering this approach to ASCT. Preferentially removing activated T cells is
an alternative approach to decreasing GVHD while maintaining a degree
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