Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 146

Because of the success demonstrated by targeting WT1 in leukemia, current
work is focusing on developing antibodies that target WT1 peptide/HLA-A2
complexes on cell surface, similar to what was developed for PR1 [10] .

RHAMM (CD168)

Receptor for hyaluronic acid-mediated motility (RHAMM) is a cytoplas-
mic protein that is poorly expressed in normal tissues but is upregulated in
response to hypoxia and stress, and is mainly associated with tissue damage
and wound repair [22] . The intracellular and surface localization of RHAMM
allows it to play a dual role, one in cell proliferation by its involvement in
mitotic spindle stabilization [23] , and also in cell migration through its inter-
actions with cell-surface proteins. In malignant cells, intracellular RHAMM
was shown to interact with BRCA1 and BARD1 [24] , thereby attenuating the
mitotic-spindle-promoting activity and driving the cells toward genomic
instability. In addition to its intracellular roles, RHAMM can be exported
to the cell surface under specific stimuli or following malignant transfor-
mation, which allows RHAMM to interact with cell-surface receptors that
have demonstrated tumor promoting properties [25] . One example of such
interaction occurs with the cell-surface receptor CD44, which mediates
signaling through its association with ERK1 and ERK2 thereby promoting
cell invasion and migration. CD44 is stabilized by partnering with RHAMM,
which leads to increased CD44-mediated tumor-enhancing signals through
ERK1 and ERK2 [25] . RHAMM was shown to be expressed in solid tumors,
AML, CML and MDS [26] . The high expression of RHAMM in malignant
cells, but not normal tissues, and its role in oncogenesis, cell migration and
invasion make it an ideal TAA for targeting in immunotherapy.

148

Numerous HLA-A2 binding peptides derived from RHAMM have been
shown to elicit humoral and cell-mediated immune responses. Greiner et al.
demonstrated immunity to two RHAMM-derived peptides, R3 (ILSLELMKL)
and R5 (SLEENIVIL), by showing peptide-specific CTL in HLA-A2-positive
patients with AML [27] . Furthermore, peptide-specific CTL lysed RHAMM
expressing targets.

In view of this promising pre-clinical data, a phase I clinical trial was con-
ducted by Schmitt et al. using R3 peptide vaccine in patients with AML/MDS
( n = 6) and multiple myeloma (MM) ( n = 4). R3 peptide vaccine was shown
to be safe, and vaccinated patients demonstrated clinical and immunologi-
cal responses [28] . A decrease in blast count or a hematological improve-
ment was shown in three of six patients with AML/MDS and an increase in
tetramer + R3-CTL was seen in four of these patients. In addition, there was a
direct correlation between achieving immunological and clinical responses.
To improve the immunological and clinical responses following the ini-
tial dose of RHAMM peptide vaccine, Greiner et al. administered a higher
dose of R3 peptide vaccine, 1000 μg and 300 μg/vaccination, to six and three
patients with AML/MDS and MM, respectively [29] . Their results showed
that the higher vaccine dose was not superior in comparison with the lower
dose of RHAMM peptide vaccine, but patients achieved immunological and
clinical responses with the higher dose. Further investigations of RHAMM
peptide vaccine are needed to better define the therapeutic potential of
RHAMM peptide vaccine in patients with hematological malignancies.