Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 149

peptide, HLSTAFARV, was shown to be immunogenic in HLA-A2 transgenic
mice and also in humans. This immunogenicity was demonstrated by the
ability of peptide-specific CTL to lyse G250/CAIX-pulsed cells or cells that
endogenously expressed G250/CAIX [51] .

Despite the immunity to G250/CAIX that was detected in leukemia
patients, most of the studies with G250/CAIX have been done in solid
tumors, specifically in RCC. In BALB/c mice, vaccinations with G250/
CAIX peptide-loaded dendritic cells (DC) resulted in rejection of RCC
tumors [52] . In a phase I clinical trial, vaccinating RCC patients with DC
that were transfected with tumor RNA elicited G250/CAIX-specific cellu-
lar immune responses. Furthermore, tumor-related mortality was lower
for patients who received the vaccine [53] . These in vivo data, although in
solid tumors, provide the impetus for further development of G250/CAIX
immunotherapy in AML.

Tumor-specific antigens

Tumor-specific antigens (TSAs) provide the ideal target for immunotherapy.
Because they are expressed solely by the tumor, targeting these antigens
would be expected to produce minimal off-target toxicities. Furthermore,
because TSA are unique to the tumor, they often play a causative role in
the malignant transformation of the cell and/or they promote malignant
cell proliferation. Therefore, immune approaches that target TSA would be
predicted to completely eradicate existing malignant clones. Furthermore,
if immune memory is elicited, targeting these antigens would prevent the
recurrence of the malignancy.

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BCR-ABL

The gene product of the BCR-ABL translocation demonstrates a prime
example of a TSA. BCR-ABL fusion (Philadelphia chromosome) results from
a translocation between chromosomes 9 and 22, t(9;22)(q34;q11). This
translocation is critical for the pathogenesis of CML, is detected in 95% of
patients with CML, and is absent in normal cells [54] . In addition to CML,
BCR-ABL can also be detected in 30% of adults with ALL and occasionally in
patients with AML [55] . The BCR-ABL translocation leads to an increase in
ABL tyrosine kinase activity, thereby providing a constitutively proliferative
cellular signal leading to the proliferation and apoptotic resistance of the
malignant clone.

The BCR-ABL fusion occurs when BCR exons 13 (b2) or 14 (b3) fuse with
ABL exon 2 (a2). The fusion transcripts are termed b2a2 or b3a2, depend-
ing on which of the two BCR exons are fused to ABL. Approximately 60%
of CML patients harbor the b3a2 rearrangement [56] , and as a result most
investigators have targeted the b3a2 fusion protein, even though immunity
can be elicited against both b2a2 and b3a2 [57] . Bocchia et al. first identified
four overlapping HLA class I peptides derived from the b3a2 fusion pro-
tein [58] . These peptides bound HLA-A3 (KQSSKALQR), A11 (ATGFKQSSK),
B8 (GFKQSSKAL) or both A3 and A11 (HSATGFKQSSK). These four pep-
tides, along with a 25-amino-acid peptide that included all four overlap-
ping sequences, were administered to patients with CML in a phase I dose