Common human cancers have been found to be frequently associated with somatic mutations in dominant and recessive oncogenes including the ras and p53 genes 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. We have developed effective methods for induction of mutant oncogene- specific CTL in animals, and have detected such responses in humans, and shown that we can induce them with peptide vaccination. In this project, we will: 1) Test the immunological efficacy of individualized, mutant p53- specific, peptide-pulsed autologous dendritic cells (DC) with concurrent IL12 in a Phase II clinical trial of adjuvant immunotherapy for small cell lung cancer patients who achieve a good response to standard therapy. 2) Immunologically and molecularly characterize mature DC from patients with SCLC on this clinical trial before and after chemotherapy. We have preliminary data which shows that DC are functionally defective in patients with cancer, but are fully functional when grown in vitro growth conditions of DC precursors for future clinical vaccine trials, and will help elucidate the mechanism of this DC dysfunction. 3) Characterize dendritic cells genetically engineered to express T-cell epitopes as an alternative to peptide pulsing for autologous cell vaccines. 4) Analyze SCLC tumors from these patients for acquired defects in the machinery of antigen presentation, particularly beta2 microglobulin. The ultimate goal of this work is to better understand human cellular immune responses to mutant oncogene products in small cell lung cancer and to develop effective clinical translational therapies, particularly in the minimal residual disease setting.
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