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

1.9 Prospect of Universal Tumor Antigens as a Clinical Target for Immunotherapy
be restricted to tumor cells themselves for the discovery of antigens. The comparison
of normal versus malignant stroma or endothelium, for example, may uncover
non-tumor derived T cell epitopes against which cellular immunotherapy can be
developed.
1.8
Prospects for Additional Universal Tumor Antigens
At least two antigens other than hTERTare already being evaluated as candidate universal
tumor antigens. Our group has preliminary data demonstrating that a carcinogen
metabolizing enzyme, a member of the cytochrome P450 gene family, is not
only widely expressed in human cancer but also a target for immune intervention (J.
L. Schultze, unpublished). Analyzing publicly available SAGE databases revealed a
marked overexpression of this gene in breast cancer cells. Analysis of more than 120
tumor samples revealed that more than 95% of tumors overexpress this protein,
whereas it is absent in nearly all normal tissues. In preliminary experiments, peptides
identified from this gene by epitope deduction have been shown to be presented
by tumor cell MHC and that the peptide-specific T cell repertoire in healthy
individuals and in cancer patients is intact (J. L. Schultze, unpublished). Similarly,
the newly identified apoptosis inhibitor protein survivin has been recognized as a
widely occurring tumor-associated antigen capable of inducing cytolytic specific
CD8 + T cells in vitro [24, 47]. At least one peptide predicted by epitope deduction was
shown to result from natural intracellular processing of survivin.
1.9
Prospect of Universal Tumor Antigens as a Clinical Target for Immunotherapy
There are several reasons to consider that universal tumor-associated antigens, characterized
by epitope deduction might offer a useful advance in the development of
cellular immunotherapy. Most directly, a wide expression across all types of tumors
would enable novel strategies for antigen-specific immunotherapy to extend to more
patients with common cancers. In the case of telomerase, HLA-A2, -A3 or -A24 is expressed
by more than 75% of cancer patients, such that nearly three quarters of all
cancer patients could already be considered for hTERT-specific therapies based on
the hTERT CTL epitopes currently described.
Second, targeting gene products vital to the oncogenic process may help to circumvent
the difficulties of immune escape. Molecules like hTERT, if restricted to tumor
cells and naturally processed for presentation by MHC, might be able to function as
effective immune targets for which mutation or loss as a means of immune escape
is incompatible with sustained tumor growth [18]. Small mutations, particularly
within targeted epitopes, as well as down-regulation or functional loss of the presenting
HLA allele, would remain problematic, of course, but these issues might be addressed
by polyepitope and polyallelic vaccines.
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