Dendritic-cell-peptide immunization provides immunoprotection against bcr-abl-positive leukemia in mice

Chronic myelogenous leukemia (CML) is a clonal disorder characterized by pr oliferation of cells that possess the bcr-abl fusion gene resulting in the production of one of two possible chimeric 210-kDa tyrosine kinase proteins . Since these chimeric proteins are expressed only in leukemic cells they h ave the potential to serve as tumor-specific antigens for cytotoxic T lymph ocytes (CTL). Using the 12B1 murine leukemia cell line, derived by retrovir al transformation of BALB/c bone marrow cells with the bcr-abl (b(3)a(2)) f usion gene, we have demonstrated that intravenous inoculation of 12B1 cells into BALB/c mice results in a disseminated acute leukemia analogous to hum an CML in blast crisis. Histological sections of liver and spleen and polym erase chain reaction analysis of peripheral blood, bone marrow, liver, sple en and lymph nodes confirmed the presence of bcr-abl(+) leukemia cells in t hese murine tissues, while Western blot data demonstrated the expression of the fusion protein in 12B1 cells. Immunization of mice with dendritic cell s (DC) loaded with the synthetic bcr-abl chimeric nonapeptide, GFKQSSKAL, l ed to a 150 times higher frequency of bcr-abl-specific CTL precursors in th e spleen than in mice immunized with peptide alone. In vitro re-stimulation of DC-peptide-primed splenocytes resulted in substantial secretion of inte rferon gamma and augmented cytolytic activity against 12B1 targets. Finally , vaccination with peptide-loaded DC significantly prolonged survival of BA LB/c mice that were challenged with 12B1 leukemia. The capacity to generate bcr-abl-specific CTL in vivo by DC-based immunization may have clinical im plications in the treatment of CML.