title: A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer.
abstract: Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which is widely expressed in a range of epithelial malignancies but is not expressed in most normal tissues. To generate high-avidity TCRs against MAGE-A3, we employed a transgenic mouse model that expresses the human HLA-A*0201 molecule. Mice were immunized with two HLA-A*0201-restricted peptides of MAGE-A3: 112-120 (KVAELVHFL) or MAGE-A3: 271-279 (FLWGPRALV), and T cell clones were generated. MAGE-A3-specific TCR α- and β-chains were isolated and cloned into a retroviral vector. Expression of both TCRs in human PBLs demonstrated Ag-specific reactivity against a range of melanoma and nonmelanoma tumor cells. The TCR against MAGE-A3: 112-120 was selected for further development based on superior reactivity against tumor target cells. Interestingly, peptide epitopes from MAGE-A3 and MAGE-A12 (and to a lesser extent, peptides from MAGE-A2 and MAGE-A6) were recognized by PBLs engineered to express this TCR. To further improve TCR function, single amino acid variants of the CDR3 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-chain in the CDR3 region of the TCR improved its functional avidity in CD4 and CD8 cells. On the basis of these results, a clinical trial is planned in which patients bearing a variety of tumor histologies will receive autologous PBLs that have been transduced with this optimized anti-MAGE-A3 TCR.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nachimuthu
authors.initials: N
authors.lastname: Chinnasamy
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Zhiya
authors.initials: Z
authors.lastname: Yu
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Frankel
authors.forename: John P
authors.initials: JP
authors.lastname: Riley
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Hong
authors.forename: Maria R
authors.initials: MR
authors.lastname: Parkhurst
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.forename: David S
authors.initials: DS
authors.lastname: Schrump
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015234:HLA-A Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology; D009363:Neoplasm Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma