Cellular immunity to the Her-2/neu protooncogene.
Her-2/neu (HER-2) is a 185-kDa receptor-like glycoprotein that is overexpressed by a variety of tumors such as breast, ovarian, gastric, and colorectal carcinomas. Overexpression of this oncogene is directly associated with malignant transformation of epithelial cells. The frequency of HER-2 overexpression varies among the different types of cancers, but universally represents a marker of poor prognosis. The critical role of HER-2 in epithelial oncogenesis as well as its selective overexpression on malignant tissues makes it an ideal target for immunotherapy. Antibodies and T cells reactive to HER-2 are known to naturally occur in patients with HER-2 positive tumors, confirming the immunogenicity of the molecule. Both antibodies as well as T cells reactive to HER-2 have been utilized for immunotherapy of HER-2 positive tumors. The "humanized" monoclonal antibody Herceptin has been tested in several clinical trials and found to be an effective adjuvant therapy for HER-2 positive breast and ovarian cancer patients. However, the frequency of patients responding to Herceptin is limited and a majority of patients initially responding to Herceptin develop resistance within a year of treatment. The use of vaccination strategies that generate T cell responses with or without accompanying antibody responses may serve to mitigate the problem. Various strategies for generating T cell-mediated responses against HER-2 are currently being examined in animal models or in clinical trials. The potential advantages of the various approaches to immunotherapy, their pitfalls, and the mechanisms by which HER-2 positive tumors can evade immune responses are discussed in this review.
Kiessling
Rolf
R
Department of Oncology, Karolinska Institutet, Stockholm, Sweden.
Wei
W Z
WZ
Herrmann
F
F
Lindencrona
J A
JA
Choudhury
A
A
Kono
K
K
Seliger
B
B
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use; D002471:Cell Transformation, Neoplastic; D002986:Clinical Trials as Topic; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D018734:Genes, erbB-2; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D005810:Multigene Family; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009928:Organ Specificity; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000068878:Trastuzumab; D019139:Tumor Escape
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006680:HLA Antigens; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab