Despite recent encouraging advances in the treatment of advanced ovarian cancer, this epithelial malignancy remains incurable for the vast majority of patients. Yet, since modern medical and surgical treatment can induce clinical remissions in most patients, the time is now to attempt innovative therapies for the treatment and eradication of minimal residual disease. Dr. Butler has chosen ovarian carcinoma as a model for the application of new concepts in tumor immunology in order to accomplish this goal. The applicant's overall hypothesis is that human epithelial adenocarcinomas can appropriately present unique tumor-associated antigens which are capable of inducing T cell responses and that these studies will form a foundation for the development of novel antigen specific therapies. In order to test this hypothesis the applicant and his co-principal investigators have developed a phase I clinical vaccine trial in an attempt to immunize ovarian cancer patients against their own tumor while they are in remission. This protocol is based on the extensive clinical experience of the applicant's institution in vaccinating cancer patients with autologous, lethally irradiated tumor cells engineered genetically engineered to secrete human GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor). With this trial as a basis for his studies, Dr. Butler plans to accomplish the following aims: 1) Identify a finite set of candidate ovarian cancer-associated antigens which may be capable of eliciting an in vivo T cell response. 2) Determine which candidate antigens/peptide sequences are targets of T cells obtained from patients following vaccination. 3) Demonstrate that tumor cells appropriately process and present candidate antigens such that they can serve as targets of cytotoxic T lymphocytes. The team of clinicians and scientists of which Dr. Butler is an important member is committed to developing a program in the immunotherapy of ovarian cancer. The breadth of research methods entailed in this project will provide an outstanding training experience in tumor immunology. The guidance Dr. Butler will receive from his mentor, as well as his collaborators, will enable Dr. Butler to mature into a leading clinician-scientist interested in translating breakthroughs in immunotherapy to the care of patients.
