Breast cancer remains 1 of the most insidious and difficult to treat human malignancies, affecting thousands of individuals each year. Our proposed studies are aimed at developing a novel tumor immunotherapy by using cryptic peptides of Her-2 protein and modified Her-2 peptides, both of which break immune tolerance to """"""""self """""""" tumor antigens expressed on breast cancer cells. In general, most tumor antigens have been characterized as normal, non-mutated self peptides, linking the concepts of autoimmunity with the development of tumor immunity. Our phase I studies have demonstrated the ability of peptide vaccination to elicit anti-Her-2 antibodies that resemble Herceptin, a monoclonal antibody currently approved for immunotherapy of human breast cancer. Similar to Her-2 binding by Herceptin, antibodies induced by peptide vaccination bind native Her-2 protein on living tumor cells and in solid phase immunoassays, as well as denatured Her-2 protein and peptides therein. We have demonstrated that immunization with Her-2 peptides elicits antibodies that inhibit tumor cell growth in vitro and in vivo. The goal of the Phase II study is to develop enhanced anti-Her-2 tumor immunity with a select group of Her-2 peptides in combination with adjuvants approved for human use, alum and novel TLR-based adjuvants. At present, antibody-mediated treatment of breast cancer requires prolonged administration of the therapeutic. This work will attempt to establish vaccine- based long term immunity with antibody specificities and biologic efficacy comparable to Herceptin therapy. The overall objective of this research is to develop peptide-based vaccination strategies to mimic the anti-tumor properties of Herceptin, an antibody with proven clinical efficacy in patients with breast cancer. ? ?
| Doyle, Hester A; Mamula, Mark J (2012) Autoantigenesis: the evolution of protein modifications in autoimmune disease. Curr Opin Immunol 24:112-8 |
