Common human cancers have been found to be frequently associated with somatic mutations in p53 and ras. 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 therefore do not have to be normally expressed on the cell surface. We have developed effective methods for induction of mutant oncogene-specific CTL in animals, have detected such responses in humans and shown that we can induce them in animals and humans with peptide vaccination. We have also found that dendritic cells are much more potent inducers of immunity than the peripheral blood mononuclear cells used in the current human clinical trial, and identified vascular endothelial growth factor (VEGF) as responsible for defective dendritic cell function in cancer patients. These findings suggest a number of approaches which can vastly improve the efficacy of peptide immunotherapy for cancer. These include the use of in vitro differentiated, peptide pulsed autologous dendritic cells, and blockade of vascular endothelial growth factor concurrent with immunization. In this proposal, we will initiate CTEP sponsored human clinical trials of custom mutant p53/ras peptide pulsed autologous dendritic cells in the adjuvant treatment of patients with poor prognosis solid tumors. The ultimate goal of this work is to develop effective clinical translational therapies, particularly in the minimal residual disease setting.
