Tumor-associated antigens - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 143

Not only is the nature of the TAA important for its immunogenic proper-
ties, but equally important are the antigen-presenting machinery of the
target cell and the degree of MHC class I expression on the target cell sur-
face. Proper antigen presentation by MHC class I is critical for recognition
of target cells by a primed immune system. For example, the presence of
antigens in specific subcellular compartments that allows them preferential
access to the MHC class I machinery, such as proteasome, can facilitate effi-
cient antigen presentation [1,2] . Ubiquitination of proteins is an important
step in antigen presentation, and TAAs that are ubiquitinated may be more
efficiently presented on MHC class I [1,3] . Furthermore, defective antigen
presentation was shown to be a mechanism for tumor escape from immune
recognition [4] .

Another feature that makes a TAA ideal for immunotherapy is the depen-
dency of the malignant cells on the expression of the TAA. Targeting TAAs
that drive the proliferation of the malignant clone will not only contribute
to the reduction of the disease burden, but will eliminate the underlying
malignant clone/stem cell, which must ultimately be eradicated for achiev-
ing cure. Tumor-specific and aberrantly expressed self-antigens have been
shown to be involved in leukemogenesis. For example, the TSA protein
derived from the BCR-ABL translocation, the hallmark feature of chronic
myelogenous leukemia (CML), has been targeted by immunotherapy with
some success. In addition, targeting Epstein-Barr virus (EBV), which is
believed to play a causal role in the pathogenesis of Hodgkin's lymphoma
(HL), has shown promising results [5] .

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Since the immunogenic epitopes of antigens are only 9-14 amino acids
that are derived from the source protein, there are two primary approaches
to target TAA. In one approach vaccines or cytotoxic T cells (CTL) are gen-
erated against known epitopes that are MHC (designated human leuko-
cyte antigen (HLA)-restricted). The advantage to this methodology is that
it provides controlled immunity against specific targets. Epitope-directed
immunity, however, is limited in that it can only be applied to distinct
patient populations that have the specific HLA locus for a particular
immunogenic peptide. The majority of epitope-directed approaches are
designed to target HLA-A2-restricted peptides, since HLA-A2 is the most
frequently occurring HLA allele found in up to 50% of Caucasians, (HLA-
A24 is the most common HLA serotype in Japan). The second approach to
target TAA involves eliciting immunity against multiple epitopes using the
entire antigen of interest, which usually employs cellular immunothera-
pies to include antigen presenting cells (APCs) and oligoclonal antigen-
specific CTL. In this approach, TAA-specific T cells are expanded by APCs
that have been pulsed with the whole antigen or tumor cell lysates. The
immune response elicited from this methodology targets naturally pre-
sented dominant epitopes and is not dependent on prior knowledge of the
HLA subtype.

In summary, TAAs have been shown to be important targets for immu-
notherapy for solid and hematopoietic malignancies. Their discovery has
allowed for the use of therapies that specifically target malignant cells,
thereby sparing normal tissues from the cytotoxic effects of non-specific
chemotherapeutic agents. Some of the essential properties of the ideal TAA