Common human cancers have been found to be frequently associated with somatic mutations in dominant and recessive oncogenes including the p53 gene, and often produce mutant oncogene proteins that are uniquely present in the patient's cancer but not in his/her normal cells. These tumor-specific proteins could form the basis for highly tumor-specific cellular immunotherapy which targets an epitope that is present in each cancer cell and is fundamental to the maintenance of the malignant phenotype. It is now known that cytotoxic T lymphocytes (CTL) detect target cells for killing by recognizing short peptide fragments of endogenous proteins which are presented to them by class I MHC molecules on the surface of the target cell. The target proteins therefore do not have to be normally expressed on the cell surface. The applicant has developed effective methods for induction of mutant oncogene-specific CTL in animals, and has detected such responses in humans and shown that he can induce them in animals and humans with peptide vaccination. The applicant also has evidence that progressively advanced stages of breast cancer are associated with defects in antigen presentation, and specifically poor dendritic cell (DC) function, associated with defects in maturation from stem cells. The applicant has discovered that this at least is partly mediated by tumor-derived VEGF production.
The specific aims of this application are: 1) continue to assess the frequency and clinical significance of anti-p53 CTL in patients with breast cancer, 2) determine the frequency and clinical significant of DC dysfunction and its relation to the development of anti-p53 CTL, and 3) characterize dendritic cells genetically engineered to express T-cell epitopes as an alternative to peptide pulsing for autologous cell vaccines.
