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Vaccines for the 21st Century: A Tool for Decisionmaking
regulating stimulated molecules and APCs. If the peptides are presented on dendritic cells, it might be possible to induce CTLs in a CD4-independent mechanism.
There is concern that inducing CTL may increase the severity of cell loss, but studies in HBV-transgenic mice indicate that passive transfer of large amounts of CTL clones does not lead to massive liver damage. There might be a patchy necrosis, in addition to a cytokine-mediated decrease in viral DNA due to IFN-gamma and TNF, but CTL does not appear to kill liver cells, even when 100 percent of those cells express antigen.
CD8 CTL TO MUTATED ONCOPROTEINS AND FUSION PROTEINS23
Mutant Proteins and Peptides as Target Antigens. Whatever the inciting carcinogenic event, most types of cancer involve either the inactivation of tumor suppressor genes or the activation of oncogenes. Often, but not always, that involves point mutations or translocations that potentially create neoantigenic determinants that might serve as tumor antigens and thereby serve as the targets of vaccines. Since these mutations or translocations would occur only in the tumor cell, they could provide unique markers that distinguish the tumor cell from normal host tissues to make a specific vaccine.
The problem with this approach, from the point of view of conventional tumor vaccine work, is that most tumor antigens have been described using antibodies, which can only recognize proteins on the surface of tumor cells. The products of these oncogenes and tumor suppressor genes are generally intracellular proteins, often nuclear proteins, that are not expressed on the surface of the cell. However, this limitation does not apply to CD8 cytotoxic T-lymphocytes (CTLs), which is able to “see” any protein synthesized in the cell. This is because those proteins, or some subset of them, are degraded into peptide fragments that are actively transported into the endoplasmic reticulum, where they bind to newly formed Class I MHC molecules and are transported to the cell surface, at which point the peptide fragments can be recognized by CD8 CTLs.
In this way, nucleo- and cytoplasmic proteins can operate as tumor antigens for CTLs. Among the many mutant proteins, researchers have thus far focused on p53 and ras, both of which occur in many of the most common types of cancer. This presentation focuses on p53; a later presentation focuses on ras (see below).
Mutant p53 Tumor Vaccine. The strategy followed was to make a short synthetic peptide spanning the site of a point mutation, and then immunize with