Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

mal tissues, except for testis; therefore, the term cancer testis antigens has been coined
for them [9]. Since it is not the whole testis organ, but only the spermatocytes that express
these antigens, the term cancer germline antigens might be more appropriate.
Many of the genes coding for these antigens exist as multi-member gene families.
The prototypes of this category, MAGE [3], BAGE [12] and GAGE [13], were initially
identified as targets for cytotoxic T cells. The HOM-MEL-40 antigen, which was detected
in a melanoma library, is the first cancer/testis antigen identified by SEREX.
It is encoded by the SSX-2 gene [8]. Members of the SSX gene family, SSX1 and
SSX2, have been shown to be involved in the t(X;18)(p11.2; q11.2) translocation
which is found in the majority of human synovial sarcomas [14] and fuses the respective
SSX gene with the SYT gene from chromosome 18. Using homology cloning,
additional members of the SSX-family were identified [15] revealing at least five
genes, of which four (SSX-1, -2, -4 and -5) demonstrate a CT antigen-like expression
[16]. Using SEREX, Chen et al. [9] identified NY-ESO-1 as a newCT antigen. NY-
ESO-1 mRNA expression is detectable in a wide array of human cancers, including
melanomas, breast cancer, bladder cancer and prostate cancer. A homologous gene,
named LAGE-1, was subsequently isolated by a subtractive cloning approach [17] demonstrating
that NY-ESO-1 belongs to a gene family with at least two members. NY-
ESO-1 as well as its homolog LAGE-1 were discovered by independent groups using
tumor specific CTL or tumor-infiltrating lymphocytes (TIL) derived from melanoma
patients as probes, thus disclosing several HLA-A0201- and HLA-A31-restricted epitopes
[18], and demonstrating that NY-ESO-1 is a target for both antibody and CTL
responses in the same patient [18, 19]. IgG antibody responses, sometimes at very
high titers (up to 1:100 000), directed against NY-ESO-1 are present in up to 50 % of
antigen-expressing patients, demonstrating the extraordinary immunogenicity of
NY-ESO-1 and proving this antigen as a frequent target for CD4 + T lymphocytes [20].
Another newCT antigen is HOM-TES-14 [10], which is encoded by the gene coding
for the synaptonemal complex protein SCP-1.
2.5.2
Differentiation Antigens
Differentiation antigens are expressed in tumors in a lineage-associated expression,
but are also found in normal cells of the same origin; examples are tyrosinase and
glial fibrillary acidic protein (GFAP), which are antigenic in malignant melanoma
and glioma [21], but are also expressed in melanocytes or brain cells, respectively.
2.5.3
Antigens Encoded by Mutated Genes
2.5 Specificityof SEREX Antigens
Antigens encoded by mutated genes have been demonstrated only rarely by the serological
approach, with mutated p53 being one example [22]. However, it is very difficult
to rule out that an antibody response detected by SEREX is not initiated by a mutated
antigen, since such antibody responses may be directed to epitopes shared between
the wild-type and mutated form of the antigen. Thus, wild-type alleles may be
21