PEPTIDE-BASED, BUT NOT WHOLE PROTEIN, VACCINES ELICIT IMMUNITY TO HER-2 NEU, AN ONCOGENIC SELF-PROTEIN/

HER-2/neu, an overexpressed oncogenic protein, has been proposed as a human cancer vaccine target. HER-2/neu is a ''self'' protein, however, and methods of vaccine strategies that would be effective in immunizi ng patients to a ''self'' tumor Ag have not been established. Many of the tumor Ags defined in humans are nonmutated self proteins, e.g., MA GE, and overcoming tolerance may be key in the generation of effective anti-tumor immunity. One theory states that tolerance to self protein s is directed only to dominant epitopes of proteins and not to every p ortion of the protein, Accordingly, tolerance can be circumvented by i mmunization to peptide fragments, but not whole protein, The studies o utlined here demonstrate rat neu-specific immunity could be elicited i n rats by Vaccination with immunogenic rat neu peptides, but not by im munization with the intact protein. A rat model was used since rat neu protein is 89% homologous to human HER-2/neu protein and has a simila r tissue distribution and level of expression. Rats were immunized wit h groups of peptides derived from the amino acid sequence of the intra cellular domain or extracellular domain of rat neu protein and both gr oups developed CD4(+) T cell immunity and Ab immunity to rat neu pepti des and protein. Animals immunized in a similar fashion with intact pu rified rat neu protein did not develop Ab or T cell immunity to rat ne u. Furthermore, rats that developed neu-specific immunity showed no hi stopathologic evidence of autoimmunity directed against organs express ing basal levels of rat neu protein, These studies suggest an immuniza tion strategy that might be effective in human cancer vaccines targeti ng self tumor Ag.