The Rational Design of T-Cell Epitopes With Enhanced Immunogenicity
For all cancer vaccine strategies, a major challenge facing efforts to induce a clinically effective T-cell response is the necessity to break tolerance to normal, “self” antigens. To control auto-reactivity, some T cells with high avidity for tumor-associated antigen (TAA) epitope—major histocompatibility (MHCs) complexes are deleted in the thymus and the remaining T cells are controlled by peripheral tolerance (1). However, several groups have demonstrated using in vitro systems that thymic-deletion of TAA-specific cytolytic T cell (CTL) is not complete (2–4). More importantly, it is clear that in some patients, natural exposure to tumor or immunization with wild-type antigens or epitopes can induce CTL of sufficient avidity and functionality to infiltrate tumors in vivo and/or recognize tumor cells in vitro. Therefore, although the fundamental vaccine strategy of targeting TAA to mount tumor-specific immune responses is supported, it remains a significant challenge to design cancer vaccine strategies that consistently overcome immunological tolerance in order to effectively activate and maintain therapeutic T-cell responses. Experimentation in the late 1980s and 1990s has resulted in a detailed understanding of the molecular mechanisms controlling T-cell activation and effector function. It is now appreciated that the interaction of a T-cell receptor with a peptide epitope presented by an antigen-presenting cell (APC) in the context of an MHC molecule generates the central event (referred to as “signal 1”) in the activation of naïve or memory T cells.
KeywordsCancer Vaccine Single Amino Acid Substitution Altered Peptide Ligand Anchor Position Human Carcinoembryonic Antigen
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