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

10 1 Search for Universal Tumor-Associated T Cell Epitopes
activated with a combination of cytokines [36]. Anti-hTERT CTL also fail to lyse activated
T cells, including phytohemagglutinin-activated CD8 + or CD4 + T cells or
hTERT + CTL themselves. As with stem cells, this finding may reflect relatively low levels
of hTERTor, alternatively, may indicate that hTERT is not properly processed and
presented in certain normal cells. In contrast, activated B cells, in either the HLA-A2
or HLA-A3 system, were susceptible to hTERT-specific lysis. Activated B cells function
well as antigen presenting cells and notably represent the only cell other than tumor
cells that to date have been demonstrated to undergo hTERT-specific lysis.
Mouse model systems have confirmed these in vitro observations. In mice vaccinated
with dendritic cells transduced with murine TERT RNA [33], anti-murine TERT prophylactic
immunity can be demonstrated in three individual tumor models. These
results are particularly interesting because of the much broader expression of TERT
in mice compared with humans. Vaccinated mice in this study were reported to remain
healthy and without injury to hematopoietic cells or other murine tissues that
express mTERT such as the liver [33].
It is not yet known whether hTERTis a tumor rejection antigen. However, if efficient
immunity can be successfully induced without the induction of autoimmunity,
hTERT clearly becomes a prime candidate for a widely applicable anti-cancer vaccine.
In the US, at least two clinical trials targeting hTERT peptide in HLA-A2 advanced
cancer patients are underway and similar trials have been initiated in Europe. A feasibility
vaccination study of hTERT peptide-pulsed dendritic cells was initiated at the
Dana-Farber Cancer Institute and a peptide/adjuvant/cytokine trial was initiated at
the National Cancer Institute. Results have not yet been reported.
1.7
Linking Cancer Genomics to Cancer Immunotherapy
hTERT represents only one example of a nearly universal tumor-associated antigen
identified by epitope deduction. Now, after the unveiling of the human genome [46],
it becomes possible to explore systematically gene products critical to the cancer process
as potential targets for immunotherapy, following the analysis of hTERT as a
guide. From advances in genomics and cancer biology, discoveries regarding genetic
regulation and dysregulation in cancer will be advanced. Facilitated by genomic and
proteomic technology, there will be sufficient data about these genes so that a direct
link can be made between genomic information and the discovery of antigens [18].
Gene expression profiling in cancer can be used to reveal overexpressed gene products
including oncogenes, mutations, fusion products, and viral genes, which are
expressed in tumor cells but not in normal tissue. Differential gene expression
analysis on the transcriptome level can be performed by a variety of techniques including
serial analysis of gene expression (SAGE), reverse transcription-polymerase
chain reaction-based differential display techniques and subtractive hybridization.
Ideal candidate genes would be restricted to the malignant phenotype, expressed
in the great majority of all human cancers and present at the earliest
stages of malignant transformation. Moreover, gene expression profiling need not