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include distinct expression by malignant cells in comparison with normal
cells, proper antigen processing and presentation on cell surface MHC,
which together lead to appropriate recognition by the immune system. The
following sections will discuss TAAs that are most relevant to the field of
allo-HSCT.
Aberrantly expressed self-antigens
Aberrantly expressed self-antigens constitute the largest group of TAAs.
Although no mutations have been detected in the amino acid sequences
of this subgroup of TAAs, their overexpression or aberrant localization
accounts for preferential processing and presentation by malignant cells.
Vaccines, adoptive cellular therapies and antibodies have been used to tar-
get these TAAs with some success. Currently, immunotherapy that targets
TAAs is not part of the standard of care approach to the treatment of hema-
tological malignancies. However, the success encountered with pre-clinical
and early clinical studies provides the stimulus for continuing investiga-
tions of TAAs in the treatment of malignancies.
146
PR1
PR1 (VLQELNVTV) is an HLA-A2 (specifically HLA*0201)-restricted
peptide derived from the azurophil granule proteases NE and P3
[6]
.
NE and P3 are expressed by normal neutrophils and in early stage hemato-
poietic myeloid cells. Additionally, NE and P3 are also aberrantly expressed
in acute myelogenous leukemia (AML) and CML
[7]
. Not only are NE and
P3 levels higher in leukemia, they are located outside azurophil granules,
which facilitates their processing and PR1 presentation on leukemia cell
surface
[1]
.
PR1 was first shown to be immunogenic by Molldrem et al. who success-
fully expanded PR1-CTL from healthy individuals and demonstrated the
ability of PR1-CTL to lyse CML blasts, but not normal bone marrow cells
[6]
.
Target lysis by PR1-CTL was shown to be HLA-A2 restricted and was corre-
lated with P3 expression by leukemia. Additionally, patients with CML who
responded to IFN-α2b or allo-HSCT were shown to have higher levels of
PR1-CTL
[7]
.
These findings led to a phase I/II clinical trial using PR1 peptide vaccine in
patients with AML, CML and myelodysplastic syndrome (MDS)
[8]
. Sixty-six
patients were entered on this study and the measured endpoints included
toxicity as well as clinical and immunological responses. The vaccine was
shown to be safe with toxicity mainly limited to injection site reactions.
Furthermore, 13 patients achieved complete remission (CR) following vac-
cination and 25 patients demonstrated ≥ two-fold increase in PR1-CTL
following vaccine administration. Achieving immunological response was
correlated with a longer event-free survival (8.7 months vs 2.4 months;
p
=
0.03); 9 of the 25 immune responders showed a clinical response. Rezvani
et al. corroborated these findings in a trial of concurrent Wilms tumor
(WT1) and PR1 peptide vaccines by showing a positive correlation between
PR1-CTL and clinical responses in three of six patients with myeloid leuke-
mia or MDS
[9]
.
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