DESCRIPTION: (Applicant's Abstract) The recent identification of several tumor-derived T-cell epitopes has provided crucial reagents for the design and implementation of peptide-based therapy protocols for the treatment of patients with certain cancers (i.e., melanoma). These trials are currently hampered due to indecision on the proper choice of peptide adjuvant and relevant immune parameters to be evaluated. The applicant has examined tumor peptide vaccines in a series of established murine tumor models and has shown dramatic tumor regressions using therapies consisting of i.v. inoculation of IL-4 + GM-CSF cultured bone marrow (BM) dendritic cells (DC) pulsed with tumor-derived peptides. Peptides may be either synthetic or unfractionated material removed from tumor cells by mild acid-elution. The therapeutic efficacy of DC/unfractionated tumor peptide vaccines involves both CD4+ and CD8+ lymphocytes, the cytokines IFN-gamma and TNF-alpha, and the CD28/CTLA T- cell costimulatory signalling pathway. Furthermore, successful DC/tumor peptide therapy was associated with pronounced perilesional infiltration with S-100+ host tissue DC. These results support the development of DC/tumor peptide-based therapies for human cancer. In order to develop these clinical trials in a rational manner the applicant proposes to: AIM 1. Establish the most effective means to apply DC/tumor peptide- based therapies in the treatment of established murine tumors and delineate the relevant immune mechanisms involved, AIM 2. Evaluate the efficacy and mechanism of action of gene-engineered DC/tumor peptide- based therapies for the treatment of established tumors, AIM 3. Evaluate the effectiveness of DC/tumor peptide- based therapy against established tumors of common genetic background and histology, but divergent in immunogenicity/tumorigenicity, AIM 4. Identify peptide species from murine BL6-class I+ variant melanoma recognized by specific CTL for use in DC-based therapies, and AIM 5. Develop clinical trials for the implementation of DC/tumor peptide-based therapy.