Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 145

The efficacy of targeting PR1 with PR1 peptide vaccine subsequently led to
the development of anti-PR1/HLA-A2 antibody. This prototype leukemia
antibody specifically recognizes the conformational epitope of PR1 in asso-
ciation with HLA-A2 [10] . Furthermore, this antibody was shown to reduce
established leukemia and to eliminate leukemia stem cell in an in vivo
mouse model [10] . Current work is underway to determine the toxicity of
anti-PR1/HLA-A2 antibody in animal models with plans for further devel-
opment in patients with AML.

Wilm's tumor gene (WT1)

WT1 is a zinc finger transcription factor that is over-expressed in AML and
CML, as well as solid tumors [11] . It is involved in cell proliferation, differ-
entiation, and apoptosis [12] . The immunogenicity of WT1 was first studied
in animal models using the WT1-derived nonamer peptides Db126, Db221
and Db235 [13] . In these studies, WT1-CTL were generated and were shown
to kill WT1-expressing, HLA-A2 + leukemia cells. To demonstrate the speci-
ficity of the WT1-CTL for leukemia, Gao et al. showed that human WT1-CTL
were able to eliminate CML CD34 + cells while sparing normal CD34 + stem
cells in non-obese diabetic severe combined immunodeficiency (NOD/
SCID) mice [14] . Targeting WT1 was shown to be applicable to other HLA-A
molecules, including HLA-A01 [15] , HLA-A0206 [16] and HLA-A2402 [17] .

147

Clinical studies have primarily focused on three HLA class I nonamer pep-
tides derived from WT1. These include the HLA-A*0201-restricted peptide
RMFPNAPYL, and the HLA-A*2402-restricted peptides CMTWNQMNL and
its modified version CYTWNQMNL. Numerous clinical trials have dem-
onstrated the safety and efficacy of WT1 HLA-A*0201-restricted peptide in
AML patients [9] . Keilholz et al. [18] administered HLA-A*0201-restricted
WT1 peptide along with keyhole limpet hemocyanin (KLH) and granulo-
cyte-macrophage colony-stimulating factor as adjuvants to 17 patients with
AML and showed complete remission in 1 patient and stable disease in 12
patients. In addition to clinical responses, there was an increase in blood
and bone marrow WT1-tetramer + CTL in 44% and 47% of patients, respec-
tively, and a reduction in disease burden as measured by WT1 mRNA levels
in 35% of patients. These results were later corroborated by Rezvani et al.
who demonstrated that the combination of WT1 and PR1 peptide vaccines
decreased disease burden, which correlated with an increase in WT1- and
PR1-CTL in patients with AML, CML and MDS [9] .

In addition to the HLA-A*0201-restricted peptide, an HLA-A*2402-restricted
WT1 peptide vaccine was studied in lung and breast cancers, as well as
AML and MDS [19] . This vaccine has shown good efficacy and low toxic-
ity in patients with leukemia. Furthermore, long-term survival (≥ 8 years)
after vaccination with WT1 peptide was demonstrated in three patients
with AML who were in molecular relapse at the time of vaccination [20] .
The authors suggested the consideration of WT1 vaccine for patients in
hematological remission and also for patients with minimal residual dis-
ease following standard AML therapy. In another study using this WT1
HLA-A*2402-restricted peptide vaccine, Hashii et al. demonstrated vaccine
efficacy following allo-HSCT in maintaining durable remission in two pedi-
atric patients with high risk acute lymphoid leukemia (ALL) and AML [21] .