Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer |
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Authors: | 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 |
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Institution: | Pathology Department, The University of Melbourne, Melbourne, Australia, ben.williams@petermac.org. |
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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. |
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Keywords: | c-Myb Colorectal cancer DNA vaccine Autoimmunity Tetanus toxin |
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