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Immunogenicity of a p210^BCR-ABL Fusion Domain Candidate DNA Vaccine Targeted to Dendritic Cells by a Recombinant Adeno-associated Virus Vector in Vitro¹

Division of Hematology and Stem Cell Transplantation [J-Y. S., S. J. F., D. S., K. K. W.], Department of General Oncologic Surgery [R. S. K.], Department of Transfusion Medicine [I. S.], and Division of Virology [S. C., K. K. W.], City of Hope National Medical Center, Duarte, California 91010

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation, which results in the expression of chimeric BCR-ABL fusion oncoproteins that are necessary for oncogenesis, unique to the leukemic clones, and represent enticing targets for immunotherapy. As a strategy for the immunotherapy of CML, we constructed a recombinant adeno-associated virus vector encoding the p210^BCR-ABL b3a2 variant fusion region with flanking sequences (CWRBA) and used it to express the BCR-ABL fusion region within primary human dendritic cells (DCs), the most potent antigen-presenting cells currently known. Peripheral blood mononuclear cells from healthy donors were primed and restimulated in vitro with autologous DCs transduced with purified CWRBA, CWRAP (negative control), or pulsed with a peptide corresponding to the fusion domain (positive control). No specific responses were generated using DCs transduced with CWRAP. In contrast, CWRBA-transduced DCs primed autologous T cells in an antigen-specific, MHC-restricted fashion to levels comparable with the positive control. CWRBA-transduced DCs elicited both cytotoxic CD4+/Th1 and CD8+ responses, although the former were more readily detected in this system. Cytotoxicity against a tumor cell line endogenously expressing the p210^BCR-ABL b3a2 variant fusion region was also demonstrable. In addition, HLA-DRB5_*0101+DRA (DR2a) was identified as a new restriction element capable of presenting the b3a2 BCR-ABL fusion region epitope. Thus, the construct developed herein may serve as a candidate vaccine for gene-based antigen-specific immunotherapy of CML and may serve as a paradigm for the use of DCs transduced with recombinant adeno-associated virus vectors encoding multiepitope immunogens for vaccine development.

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