Induction of determinant spreading and of Th1 responses by in vitro stimulation with HER-2 peptides

Immunization with tumor antigens induces cellular and humoral immune respon ses. These responses by T cells are specific for defined epitopes (determin ants) in the molecule of the immunizing tumor antigen. Extension of such re sponses to self-antigens requires induction of autoimmunity to the tumor. A s with systems of autoimmune disease, expression of T cell autoimmunity is charaterized by diversification of responses from the inducer determinant t o other responder (cryptic) determinants. Since similar strategies may be u seful for therapy of human cancers, we investigated whether the induction o f response to a HER-2 peptide F7 (776 789) induces enhanced reactivity of o ther HER-2 peptides. We found that stimulation with F7 can expand a respons e to another epitope F13 (884-899) in both an ovarian cancer patient with p rogressive disease and a healthy donor who shared HLA-DR11. This response w as characterized mainly by increased interferon gamma secretion, and prolif eration, but was not observed with another donor who shared HLA-DR14 and HL A-DQ5 with the patient. Since repeated vaccination with the same epitope ma y lead to a decline of primary cell reactivity caused by apoptosis spreadin g the response to other epitopes, the tumor antigen may provide an approach for maintaining an inflammatory Th1 response during cancer vaccination.