Ras oncogenes are mutated in 15-20% of human cancers. Mutations in ras oncogenes are usually single nucleotide substitutions that result in the expression of ras proteins with single amino acid substitutions. Mutant ras proteins have been defined as cancer specific antigens in two ways. First, in animal models, immunity to mutant ras protein can be elicited by immunization to mutant ras peptides and proteins. Second, in humans, immunity to mutant ras proteins has been observed in patients with cancers normally associated with ras mutations. Detection of immunity to ras in patients with cancer strongly implies that patient's own cancer cells can act as a source of immunizing protein and begs the issue of whether existent immune responses to ras play any role in slowing cancer progression and whether boosting of immune responses can offer any therapeutic benefit. The current proposal will explore issues important for developing ras specific vaccines and T cell therapy. In addition, the demonstration of immunity to ras offers the opportunity to explore host- tumor interactions in a well-defined antigen system.
The specific aims are: (l) To use primary in vitro immunization with human dendritic cells to generate CD8+ CTL specific for ras peptides and proteins. (2) To use primary in vitro immunization with human dendritic cells to generate CD4+ helper T cells specific for ras peptides and proteins. (3) To evaluate existent helper T cell immunity to mutant ras proteins in patients with cancer. (4) To evaluate antibody immunity to ras proteins in patients with cancer. (5) To determine whether compounds that inhibit ras isoprenylation, such as lovastatin, can increase the susceptibility of ras positive cancers to T cell therapy. (6) To determine whether immunity to ras influences the induction of ras-positive malignancies by carcinogens in rodent models.
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