Combining human and rat sequences in her-2 DNA vaccines blunts immune tolerance and drives antitumor immunity.
Immune tolerance to tumor-associated self-antigens poses a major challenge in the ability to mount an effective cancer vaccine response. To overcome immune tolerance to HER-2, we formulated DNA vaccines that express both human HER-2 and heterologous rat Neu sequences in separate plasmids or as single hybrid constructs that encode HER-2/Neu fusion proteins. Candidate vaccines were tested in Her-2 transgenic (Tg) mice of BALB/c (BALB), BALB/cxC57BL/6 F1 (F1), or C57BL/6 (B6) background, which exhibit decreasing immune responsiveness to HER-2. Analysis of various cocktails or hybrid vaccines defined a requirement for particular combination of HER/2/Neu sequences to effectively prime immune effector cells in HER-2 Tg mice. In B6 HER-2 Tg mice, rejection of HER-2-positive tumors protected mice from HER-2-negative tumors, providing evidence of epitope spreading. Our findings show that a strategy of combining heterologous antigen with self-antigens could produce a potent DNA vaccine that may be applicable to other tumor-associated antigens.
Jacob
Jennifer B
JB
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Quaglino
Elena
E
Radkevich-Brown
Olga
O
Jones
Richard F
RF
Piechocki
Marie P
MP
Reyes
Joyce D
JD
Weise
Amy
A
Amici
Augusto
A
Wei
Wei-Zen
WZ
D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics*; D005260:Female; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D019444:Vaccines, DNA / Q000276:immunology*
D019496:Cancer Vaccines; D019444:Vaccines, DNA