Tumor induced anorexia/weight loss contributes to the morbidity and mortality of cancer and is thought to be mediated by cytokines released by the tumor-bearing host, though the evidence supporting this theory is equivocal. Immunotherapy of cancer, such as treatments utilizing gene- modified tumor cells as tumor vaccines, may increase anti-tumor immune responses, including cytokines synthesis. To date, no one has examined the systemic effects of tumor vaccines on the tumor-bearing host. The goal of this program of study is to gene modify human melanoma cells to increase expression of MHC molecules, the co-stimulatory B7-1 molecule, and melanoma antigens recognized by T cells, and determine the effects of these genetic modifications on expression of anorexigenic cytokines in tumor cells, autologous blood leukocytes and spleen cells of tumor bearing mice. Human melanoma cells will be modified in vitro using particle mediated transfer of genes for interferon-gamma, the co-stimulator B7-1 molecule, and melanoma specific antigens MART-1 and tyrosinase. Autologous and allogeneic lymphocytes co-cultured in vitro with melanoma, as well as spleen cells of SCID mice inoculated with human melanoma cells, will be examined for expression of interleukin 1 and 6, tumor necrosis factor, leukemia inhibitory factor, and interferon-gamma. The systemic effects of modified and unmodified tumor cells on body weight of tumor bearing mice will be determined, and post vaccination sites will be examined by rt-pcr for cytokine transcripts. The study will be conducted at the University of Wisconsin Comprehensive Cancer Center (UWCCC) where Dr. Mark Albertini, the sponsor, is director of the melanoma clinic and has NIH support to study gene therapy of human melanoma. Dr. McCarthy is an associate professor in the UW School of Nursing and proposes to receive training in techniques of molecular biology in this study evaluating expression of cytokines thought to contribute to tumor-induced anorexia/weight loss. Understanding the mechanisms of this clinical problem is requisite to appropriate nursing interventions to meet the nutritional needs of hypophagic cancer patients.
