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

12 1 Search for Universal Tumor-Associated T Cell Epitopes
Third, host T cell responses to antigens characterized by epitope deduction may be
naÒve and therefore less likely to be limited by anergy or tolerance. Our data suggests,
for example, that hTERT-specific T cells in cancer patients are spared functional inactivation
in vivo owing to immunological ignorance. Of course, a naÒve precursor T
cell frequency to hTERTor other similar antigens would impose upon any therapeutic
strategy the need to prime specific response in patients, which may be far more
difficult than boosting ongoing anti-tumor responses against ªrecallº tumor antigens.
Finally, and probably most importantly, the characterization of universal tumor-associated
antigens opens the door to consideration of preventative immunotherapy [18].
Although new candidate antigens are necessarily tested for safety in a therapeutic
clinical setting, it is an important reminder that post-exposure vaccination is rarely,
if ever, clinically effective. In cancer patients, tumor burden negatively impacts attempts
at therapeutic vaccination and, accordingly, there is considerable effort to test
strategies that pass phase Isafety testing in patients with minimal residual tumor
[11]. Cancer risk assessment based on genetic factors and medical history is a fastgrowing
and rapidly expanding part of clinical oncology, and therefore, it makes
sense that the first preventative cancer vaccines may be tested in individuals at highrisk
for cancer. Any preventative cancer vaccine would require a very narrow toxicity
profile and it remains to be seen if this is truly possible when targeting antigens expressed
even at low levels in normal tissue. Nevertheless, immunoprevention should
be a major goal and one that necessarily requires knowledge of the targeted antigen
up front. Any vaccine or immunotherapeutic strategy that requires autologous tumor
cells as part of the formulation ± whether for gene transfer, cell fusion, DNA extraction
or otherwise ± obviously mandates that patients already have a diagnosis of
cancer, for which a truly preventative approach is essentially impossible to envisage.
1.10
Conclusions
Clinically successful specific cancer immunotherapy depends on the identification
of tumor regression antigens. Historically, tumor antigens have been identified by
either analyzing cancer patients` own T cell or antibody responses. The unveiling of
the human genome, improved bioinformatics tools and optimized immunological
analytical tools have made it possible to screen any given protein for immunogenic
epitopes. These advancements enable the characterization of universal or nearly universal
tumor-associated gene products that mediate critical functions for tumor
growth and development. The extent to which the telomerase reverse transcriptase
hTERT represents a prototype for this new class of tumor antigens remains to be
seen; however, immunological profiling of hTERT and other candidate antigens justifies
efforts to begin testing this hypothesis in the clinic. Universal tumor antigens
represent one hope for immunoprevention of cancer.