Immunogenic HER-2/neu peptides as tumor vaccines

Abstract

During the last decade, a large number of tumor-associated antigens (TAA) have been identified, which can be recognized by T cells. This has led to renewed interest in the use of active immunization as a modality for the treatment of cancer. HER-2/neu is a 185-KDa receptor-like glycoprotein that is overexpressed by a variety of tumors including breast, ovarian, lung, prostate and colorectal carcinomata. Several immunogenic HER-2/neu peptides recognized by cytotoxic T lymphocytes (CTL) or helper T lymphocytes (TH) have been identified thus far. Patients with HER-2/neu over-expressing cancers exhibit increased frequencies of peripheral blood T cells recognizing immunogenic HER-2/neu peptides. Various protocols for generating T cell-mediated immune responses specific for HER-2/neu peptides have been examined in pre-clinical models or in clinical trials. Vaccination studies in animals utilizing HER-2/neu peptides have been successful in eliminating tumor growth. In humans, however, although immunological responses have been detected against the peptides used for vaccination, no clinical responses have been described. Because HER-2/neu is a self-antigen, functional immune responses against it may be limited through tolerance mechanisms. Therefore, it would be interesting to determine whether abrogation of tolerance to HER-2/neu using appropriate adjuvants and/or peptide analogs may lead to the development of immune responses to HER-2/neu epitopes that can be of relevance to cancer immunotherapy. Vaccine preparations containing mixtures of HER-2/neu peptides and peptide from other tumor-related antigens might also enhance efficacy of therapeutic vaccination.

Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties

“…As shown in Fig. 1, A and B, this peptide exhibited a comparable strong binding and stabilization capacity compared with peptides having high binding activity for HLA-A*0201 molecules, such as HER-2(9 369 ), which represents an immunogenic epitope of HER-2/neu (9,12,14) and flu (58 -66) (24).…”

“…In particular, HER-2/neu is present in high proportions of tumor cells (7) and single tumor cells frequently show an intense expression of this molecule (8), suggesting that anti-HER-2/neu therapy would specifically target most tumor cells. Furthermore, CTL and IgG specific for HER-2/neu have been detected in patients with HER-2/neu ϩ breast cancer (9), demonstrating that this molecule is capable of inducing both cellular and humoral immune responses in vivo. Finally, tumor-reactive CTL responses have been induced in vitro using various MHC class I-binding synthetic peptides derived from the HER-2/neu sequence (9).…”

“…Furthermore, CTL and IgG specific for HER-2/neu have been detected in patients with HER-2/neu ϩ breast cancer (9), demonstrating that this molecule is capable of inducing both cellular and humoral immune responses in vivo. Finally, tumor-reactive CTL responses have been induced in vitro using various MHC class I-binding synthetic peptides derived from the HER-2/neu sequence (9). Vaccination trials with HER-2/neu CTL peptides have in their majority included epitope p369 -377 (10 -12).…”

Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/ neu by human dendritic cells

“…The tumor-associated Ag, HER2/neu, is a clinical target of high interest. 18 It is overexpressed by a wide range of tumors, such as breast, ovary and renal cell carcinomas, and colorectal and pancreatic adenocarcinomas, [19][20][21] and it is the target for a humanized monoclonal antibody in clinical use and capable of impacting tumor growth. 19 As humoral and cellular responses against HER2/neu are detected in almost all patients, it is targeted by immune responses of the patients.…”

“…20,22 The epitope HER2/neu 369-377 , which binds HLA-A2, was found to be one of the immunodominant epitopes of the protein. 21,23 HER2/neu 369-377 is generated and presented by HLA-A2…”