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

these immune responses [3]. Although the critical role of MHC class I-restricted
CD8 + T cells in tumor rejects had been demonstrated in animal models and in cancer
patients previously [30±32], the specific function and dominant role of these cells
could be proven only after the first tumor-associated T cell epitopes and the corresponding
antigens had been identified [33, 34]. In parallel developments, great progress
has been made in the understanding of the differentiation and physiology of
effector T cells, and of the cellular and molecular requirements of the induction and
activation of these cells. This knowledge has been used for a rational development
and thorough evaluation of new vaccination therapies, although many aspects of the
T cell biology in antitumor immune responses still await elucidation.
The development of vaccination strategies for cancer immune therapy has to design
vaccines that combine relevant TAAs with a means to induce efficient T cell responses.
Hybrid cell vaccination (HCV) as one of these vaccination strategies uses
the patient's tumor cells as antigen, and renders them immunogenic and into potent
T cell stimulators by fusion with antigen-presenting cells (APCs) such as dendritic
cells (DCs) [35]. In this chapter we will discuss the immunological basis and the results
of the initial preclinical and clinical studies of this therapeutic approach.
11.2
Immunological Basis of the HCV Approach to Cancer Immune Therapy
11.2.1
Tumor Antigenicity
11.2 Immunological Basis of the HCV Approach to Cancer Immune Therapy
After several reports of clear but indirect evidence for TAAs recognized by cytotoxic
T cells in cancer patients [31, 32, 36] and the demonstration of a tumor-associated T
cell epitope in a mouse tumor model [33], the first human TAA was identified by
Thierry Boon et al. and published in 1991 [34]. Since that time about 250 tumor-associated
T cell epitopes derived from about 60 different proteins have been reported
[37, 38]. The vast majority of the antigens were identified for melanoma and are
MHC class I-restricted. Some of the antigen originally found for melanoma have later
also been demonstrated in other tumors. According to the source and expression
pattern TAAs can be classified as follows:
Differentiation antigens: proteins expressed by all cells of the tumor histotype lineage
(e.g. tyrosinase, gp100, MART/Melan) [39±45].
Embryonic antigens: epitopes derived from antigens normally expressed in embryonic
cells (e.g. CEA, AFP) [46, 47].
Tumor-testis antigens: epitopes of proteins expressed by the tumor cells and cells of
the testes (e. g. MAGE, BAGE, GAGE) [34, 48±50].
Over-expressed cellular proteins: the presentation of peptides due to over-expression of
a protein (e.g. HER-2/neu) [46, 51±54].
Antigens resulting from mutations: antigens induced by mutations in the tumor cells
(e.g. cdk4, MUM, idiotypes) [55±57].
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