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

4.6
Concluding Remarks
4.6 Concluding Remarks
Important progress in the systematic analysis of T cell-mediated immunity against
human tumors has finally led to the identification of the targets involved. To date,
well over 50 different tumor antigens have been defined at the molecular level. These
include both MHC class I- and II-restricted epitopes that can be effectively mimicked
by well-defined synthetic peptides. Although some of the antigenic peptides identified
thus far represent mutated sequences that uniquely occur in individual tumors,
the majority of antigenic peptides are in fact non-mutated self-antigens. Thus tumor
immunity can be regarded more as a special case of autoimmune reaction. This fact
has important implications. On one hand, interesting observations in some paraneoplastic
syndromes would suggest that damage of normal tissue is mediated, at least
in part, by T cells directed against antigens whose expression is shared by certain
normal cell types and the target tumor cells [94]. It is also possible that the observed
increased incidence of vitiligo in melanoma patients treated with high-dose IL-2 [95]
reflects the destruction of melanocytes mediated by immunity triggered by the transformed
melanocytes. On the other hand, effective antitumor immunity may be limited
to variable extents by the processes of central and peripheral tolerance that are
essential to avoid the potentially devastating effects of autoimmunity.
The search for new tumor antigens continues. The initial studies which focused on
CD8 T cell responses to melanoma have now been extended to many other types of
tumors, and to the analysis of specific antibody and CD4 T cells responses. New technologies
are constantly applied to this endeavor. Improved reverse immunology approaches
for the accurate forecast of new T cell epitopes will be of special value to
mine the human genome, soon to be completed and freely available in public databases.
The main objective of these efforts is to identify good candidates for the design
of cancer vaccines. The ideal candidates should be expressed in a wide variety of
tumors and yet absent in normal tissues. They should be efficiently processed by
both tumor and professional antigen presenting cells. They should also be strong
immunogens, a quality that may critically depend on both their ability to stably bind
to MHC molecules and the existence of minimal specific immune tolerance. It is
likely that only few in a large palette of tumor antigens may meet these qualities.
The molecular identification of Tcell-defined tumor antigens has ushered a new era
in tumor immunology. It has provided targets for the design of specific cancer vaccines.
Numerous phase I clinical trials of immunization have been completed recently
with encouraging results and many more are underway. New adjuvants and
antigen delivery systems are being developed. One of the most important advances
is the ability to monitor antigen-specific T cells in cancer patients. Direct flow cytometry
based assays such as tetramers and cytokine release assays allow the enumeration
and functional characterization of single antigen-specific T cells directly ex vivo.
Results from analyses based on these new tools provide convincing evidence for the
existence of frequent natural immune responses against tumors in cancer patients.
It is now clear that patients often mount immune responses against their tumors.
These can be mediated by both CD8 and CD4 T cells, and target multiple antigens,
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