Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 151

B production. In all five normal subjects, the response to the vaccine was
similar to that measured in CML patients, thereby raising concern regard-
ing the immunogenicity of the BCR-ABL peptide vaccine. These results also
confirmed a report showing that BCR-ABL was not an immunodominant
antigen in CML [68] , thus explaining the moderate clinical and immuno-
logical responses noted following BCR-ABL vaccines.

Another approach to elicit BCR-ABL immunity in CML patients has been
tried using a cellular technique, specifically peptide-pulsed DCs. Because
DCs are the most efficient type of APC, and since leukemia patients often-
times have quantitative and qualitative immune defects, pulsing DCs with
peptide and then administering the DCs to patients has the advantage of
bypassing some of the immune defects that may be encountered in these
patients. Three different methodologies were compared by Takahashi
et al. using DC-based BCR-ABL vaccine [69] . In one approach, patient DCs
were purified, loaded with BCR-ABL peptide and re-infused into patients
intravenously. In the other two approaches, DCs were either purified from
patients, pulsed with BCR-ABL peptide and then administered to patients
intradermally or matured with tumor necrosis factor-α (TNF-α) and then
administered intradermally. Despite eliciting immunologic responses,
there were no clinical responses using these approaches. Because of the
lack of clinical response, the potential of BCR-ABL targeting immunothera-
pies to elicit and maintain immunological and clinical responses needs fur-
ther investigation.

153

PML-RAR α

The promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARα)
fusion that is caused by translocation to (15;17) is a hallmark feature of acute
promyelocytic leukemia (APL). The fusion protein caused by this transloca-
tion functions as an abnormal retinoid receptor with aberrant transcrip-
tional regulatory properties [70] . As a result, the expression of PML-RARα
abrogates retinoic acid induced myeloid differentiation, causes maturation
arrest at the promyelocyte stage and protects the hematopoietic progenitor
cells from undergoing apoptosis [71] .

Because of its unique expression by malignant cells and its involvement
in the pathogenesis of APL, PML-RARα could have the potential to be an
effective immunotherapeutic target. However, there has been a paucity of
published studies that further investigates its role as a TSA and the pub-
lished reports have been somewhat contradictory. In one report, an HLA-
DR11-restricted 25-amino-acid peptide derived from the PML-RARα fusion
protein was identified and shown to be recognized by CD4+T + T cells [72] .
However, a subsequent report showed that this peptide was recognized
by normal subject, but not patient, CD4 + T cells [73] . Many years following
these original reports, Cen et al. demonstrated cellular immune responses
in BALB/c mice following the administration of a DNA vaccine encoding
PML-RARα and human interleukin (IL)-2 genes [74] . Based on these data,
the potential of PML-RARα to be an immunotherapeutic target remains
unclear. It is possible that the PML-RARα native fusion protein in itself may
be minimally immunogenic and that new technologies should be imple-
mented to augment the immune response against this TSA.