Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 148

[37] . Furthermore, high PRAME mRNA level has been correlated with
improved outcomes in patients with AML [38] , but not in CML, where an
elevated level was correlated with disease progression and blast crisis [39] .

Using proteasome cleavage pattern analysis, four HLA-A2 binding epit-
opes derived from PRAME were identified [40] , which include VLDGLDVLL
(PRA100), SLYSFPEPEA (PRA142), ALYVDSLFFL (PRA300) and SLLQHLIGL
(PRA425). Using these peptides, PRAME-specific CTL expanded from
healthy individuals lysed PRAME-expressing renal cell carcinoma (RCC),
melanoma, lung cancer and mammary cell lines. Furthermore, cellular
immunity to PRAME peptides was shown in melanoma patients and nor-
mal individuals [41] .

Immunity to PRA300 in hematological malignancies was demonstrated fol-
lowing allo-HSCT with detection of low-frequency PRA300-CTL in patients
with AML and MDS [42] . In addition, PRAME-CTL that were expanded from
normal subjects and CML patients lysed primary CML cells and PRAME-
expressing tumor cell lines [43] . In another study, PRAME-CTL were
detected in ALL, AML and CML patients, and the avidity of the PRAME-
CTL for the PRAME-derived peptides was inversely correlated with PRAME
expression in patients [44] , suggesting selective deletion of high-avidity
PRAME-CTL by leukemia that expresses high levels of PRAME. This is a
mechanism by which leukemia shapes the immune response to promote
leukemia growth.

150

Although PRAME peptide vaccines have yet to be tested in leukemia
patients, the availability of multiple immunogenic epitopes that have elic-
ited immune responses makes this protein a good potential immunothera-
peutic option for the management of myeloid leukemia. Two other cancer
testis antigens, NY-ESO-1 and MAGE, have been clinically targeted in solid
malignancies. Although immunity against NY-ESO-1 and MAGE has been
shown in leukemia and lymphoma and both TAAs appear to be promising
in hematological malignancies [45] to date, there have been no clinical tri-
als studying the efficacy of these two cancer testis antigens in hematological
malignancies.

G250/CA IX

G250/Carbonic anhydrase IX (CAIX) is a zinc metalloenzyme that cata-
lyzes the reversible hydration of carbon dioxide. G250/CAIX is regulated by
hypoxia-inducible factor-α, and its expression is higher under hypoxic con-
ditions [46] . Although most studies have shown that G250/CAIX is highly
expressed in solid malignancies, it was also shown to be highly expressed in
AML [47] . Furthermore, high expression of G250/CAIX on AML blasts was
correlated with improvement in overall survival [48] .

The expression of G250/CAIX in normal tissues is somewhat controver-
sial, for many investigators believe that high expression of G250/CAIX in
non-malignant tissue is driven by hypoxia, making these tissues abnormal
despite their non-malignant phenotype [49] . Furthermore, in some malig-
nancies G250/CAIX expression is believed to be greater, more homogenous
and demonstrates a higher membranous localization (versus cytoplasmic)
in contrast to normal tissue [50] . The HLA-A2-restricted G250/CAIX-derived