title: The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors.
abstract: One approach to development of specific cancer immunotherapy relies on the induction of cytotoxic T lymphocytes (CTL) specific for tumor-associated antigens (TAA). Induction of TAA-specific CTL could be used towards the eradication of established tumors, or to prevent their dissemination or recurrence after primary treatment. The present study identifies a set of CTL epitopes from TAA frequently found on solid epithelial tumors such as breast, lung and gastro-intestinal tumors. Specifically, HLA-A2.1 binding peptides from the MAGE2, MAGE3, HER-2/neu and CEA antigens were tested for their capacity to elicit in vitro anti-tumor CTL using lymphocytes from normal volunteers and autologous dendritic cells as antigen-presenting cells. A total of 6 new epitopes (MAGE2[10(157)], MAGE3[9(112)], CEA[9(691)], CEA[9(24)], HER2[9(435)] and HER2[9(5)]) were identified which were capable of specifically recognizing tumor cell lines lines expressing HLA-A2.1 and the corresponding TAA. In one case (CEA[9(24)]), induction of vigorous anti-tumor CTL responses required epitope engineering to increase HLA-A2.1 binding affinity. Finally, most of the newly identified epitopes (5 out of 6) were found to be highly crossreactive with other common HLA alleles of the A2 supertype (A2.2, A2.3, A2.6 and A6802), thus demonstrating their potential in providing broad and non-ethnically biased population coverage. The results are discussed in the context of the development of multi-epitope-based therapies with broad applicability for patients suffering from commonly found tumors.
authors.affiliation: Cytel Corporation, San Diego, California 92121, USA.
authors.forename: I
authors.initials: I
authors.lastname: Kawashima
authors.forename: S J
authors.initials: SJ
authors.lastname: Hudson
authors.forename: V
authors.initials: V
authors.lastname: Tsai
authors.forename: S
authors.initials: S
authors.lastname: Southwood
authors.forename: K
authors.initials: K
authors.lastname: Takesako
authors.forename: E
authors.initials: E
authors.lastname: Appella
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: E
authors.initials: E
authors.lastname: Celis
mesh_terms: D015295:Antigens, Tumor-Associated, Carbohydrate / Q000096:biosynthesis / Q000276:immunology*; D001943:Breast Neoplasms / Q000737:chemistry / Q000628:therapy; D003110:Colonic Neoplasms / Q000737:chemistry / Q000628:therapy; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000302:isolation & purification*; D005260:Female; D005434:Flow Cytometry; D005770:Gastrointestinal Neoplasms / Q000737:chemistry / Q000628:therapy; D015789:HLA-A2 Antigen / Q000235:genetics*; D006801:Humans; D007120:Immunochemistry; D016219:Immunotherapy, Adoptive; D008175:Lung Neoplasms / Q000737:chemistry / Q000628:therapy; D016133:Polymerase Chain Reaction
chemical_list: D015295:Antigens, Tumor-Associated, Carbohydrate; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen