Erschienen in:
01.11.2008 | Original Article
Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer
verfasst von:
Benjamin B. Williams, Meg Wall, Rebecca Yu Miao, Brenda Williams, Ivan Bertoncello, Michael H. Kershaw, Theo Mantamadiotis, Michelle Haber, Murray D. Norris, Anand Gautam, Phillip K. Darcy, Robert G. Ramsay
Erschienen in:
Cancer Immunology, Immunotherapy
|
Ausgabe 11/2008
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Abstract
Overexpression of the proto-oncogene c-Myb occurs in more than 80% of colorectal cancer (CRC) and is associated with aggressive disease and poor prognosis. To test c-Myb as a therapeutic target in CRC we devised a DNA fusion vaccine to generate an anti-CRC immune response. c-Myb, like many tumor antigens, is weakly immunogenic as it is a “self” antigen and subject to tolerance. To break tolerance, a DNA fusion vaccine was generated comprising wild-type c-Myb cDNA flanked by two potent Th epitopes derived from tetanus toxin. Vaccination was performed targeting a highly aggressive, weakly immunogenic, subcutaneous, syngeneic, colon adenocarcinoma cell line MC38 which highly expresses c-Myb. Prophylactic intravenous vaccination significantly suppressed tumor growth, through the induction of anti-tumor immunity for which the tetanus epitopes were essential. Vaccination generated anti-tumor immunity mediated by both CD4+ and CD8+ T cells and increased infiltration of immune effector cells at the tumor site. Importantly, no evidence of autoimmune pathology in endogenous c-Myb expressing tissues was detected as a consequence of breaking tolerance. In summary, these results establish c-Myb as a potential antigen for immune targeting in CRC and serve to provide proof of principle for the continuing development of DNA vaccines targeting c-Myb to bring this approach to the clinic.