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

232 11 Hybrid Cell Vaccination for Cancer Immune Therapy
Viral antigens: antigens derived from oncogenic viruses (e.g. human papilloma virus)
[58±60].
Of these categories, the first four are public antigens, which are not restricted to the
tumors cells. Embryonic antigens and antigens of the tumor-testis group are relatively
tumor-specific as they are either not expressed in normal adult tissue (embryonic
antigens) or, besides the tumor, only in the immune-privileged organ testis (tumor-testis
antigens). However, differentiation antigens which often dominate antitumor
immune responses are expressed also by normal adult tissue. Thus, expectedly,
autoimmune reactions against normal melanocytes are seen in some melanoma patients
[61]. These autoimmune responses were shown to be mediated by the same T
cell clones that are found among the tumor-infiltrating lymphocytes of the melanoma
lesion [62±65]. Sometimes such autoimmune responses occur in the context
of a vaccination therapy. Cytotoxic T cells with specificity for differentiation antigens
should, according to conventional knowledge, not exist. They should have been
eliminated in the course of the establishment of self-tolerance. To explain their existence
in cancer patients and even in healthy individuals [28, 29] it has been proposed
that their antigen receptors might be of low avidity and the T cells thus of too low efficiency
to eliminate the tumor cells.
T cell epitopes resulting from tumor-specific mutations are private to the tumor and,
therefore, ideal targets for immune therapy. Studies in mouse tumor models suggest
that these tumor-specific mutations might be most important for antitumor immune
responses [33, 66]. However, only very few such mutated epitopes have been identified
for human cancer. Viral antigens play a role only in those cases in which oncogenic
viruses are involved in tumorigenesis. They may, however, be interesting target
structures for the development of preventive cancer vaccines in these cases.
The majority of the tumor-associated T cell epitopes have been identified using tumor-specific
T cells as indicator cells. Serological responses to cancer, however, have
long been described and exploited in cancer diagnostic. The very systematic approach
to identifying serological antitumor specificity SEREX (see Chapter 2) has
yielded a large number of antigens recognized by antibodies of the serum of cancer
patients. Although there are a few cases in which a serologically identified antigen
also harbors epitopes for MHC class I-restricted T cells [19, 67], for the majority of
these antigens, no MHC class I-restricted T cell epitopes have so far been found.
The identification of these TAAs and T cell epitopes and their use to study the tumor-specific
immune responses in cancer patients have confirmed that CD8 + cytotoxic
T cells are the most important effector cells in antitumor immunity. After most
of the initial work to elucidate the function of these cells in cancer immunity was
done in melanoma, increasing evidence is now being presented that demonstrates
tumor-specific CD8 + T cell responses in other tumors [27, 46, 47, 51±60]. In contrast
to the large number of MHC class I-restricted epitopes, only a few MHC class II-restricted
T cell epitopes have been identified to date [38, 68, 69]. Many of the cited studies
have shown that the tumor cells display a complex antigenicity and that the immune
responses directed against the tumor cells are of correspondingly complex
specificity [70]. This complexity is further emphasized by the heterogeneity of the tu-