Biology Reference
In-Depth Information
Mutated self-antigens
Similar to tumor-specific antigens, mutated self-antigens also provide
good targets for immunotherapy since they are specific for malignant
cells. A few mutations have been documented in AML that were shown
to be of prognostic value, especially in patients with a normal karyo-
type. Fms-like tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), KIT and
CCAAT/enhancer binding protein alpha (CEBPA) are the most well-stud-
ied mutations in AML. FLT3 is a transmembrane tyrosine kinase receptor
that is involved in cell proliferation. Mutations in FLT3 lead to ligand-
independent activation of FLT3, are found in 30% of adult patients with
AML and are associated with a poor prognosis
[75]
. NPM1 gene product
is involved in numerous functions including ribosome biogenesis and
transport, genomic stability and DNA repair, and regulation of apoptosis.
NPM1 mutations are found in 50% of AML patients that have a normal
karyotype and are associated with improved clinical outcomes. KIT is a
proto-oncogene receptor tyrosine kinase that binds stem cell factor and is
involved in cell survival, proliferation and differentiation. KIT mutations
are detected in 20-30% of AML patients with t(8;21) or inversion (inv)
(16), and are associated with poor outcomes. CEBPA encodes a transcrip-
tion factor that is important in myeloid differentiation. CEBPA mutations
are found in 10% of patients with AML and are associated with improved
outcomes.
154
Since these mutated self-antigens are exclusive to the malignant cell and
play a critical role in the pathogenesis of the malignancy, theoretically they
provide the ideal target for immunotherapy. These mutations have been
targeted by non-immunological therapies (e.g. tyrosine kinase inhibitors in
AML harboring KIT mutations), but to date, there have been no immuno-
therapies that directly target these mutations.
Cellular approaches to targeting TAA
One of the disadvantages of enhancing immunity against specific epit-
opes within TAA is that the expression of the epitopes is HLA-restricted.
Specifically, the immunogenic amino acid sequence that is expressed
on the cell surface in association with HLA differs between individuals
depending on their HLA type, even though the parent proteins share
identical sequences. Furthermore, although the HLA peptide binding
algorithms that are used to predict immunogenic HLA-restricted peptides
are very accurate, the predicted peptide may not necessarily be the domi-
nant peptide presented by the cells from the parent proteins. To bypass
these limitations, tumor cells/lysates have been used in vaccine prepa-
rations to elicit immunity against naturally processed peptides, without
HLA-restriction.
Tumor cell vaccines
The GVAX platform for vaccine development has provided the meth-
odology for improving immunotherapies that target TAA. In this meth-
odology, tumor cells transduced with granulocyte/monocyte-colony
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