title: The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble antigen in serum.
abstract: In this study we aimed to determine the suitability of the Lewis-Y carbohydrate antigen as a target for immunotherapy using genetically redirected T cells. Using the 3S193 monoclonal antibody and immunohistochemistry, Lewis-Y was found to be expressed on a range of tumors including 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, and 25% colorectal adenocarcinoma. Expression levels varied from low to intense on between 1% and 90% of tumor cells. Lewis- was also found in soluble form in sera from both normal donors and cancer patients using a newly developed enzyme-linked immunosorbent assay. Serum levels in patients was often less than 1 ng/mL, similar to normal donors, but approximately 30% of patients had soluble Lewis-Y levels exceeding 1 ng/mL and up to 9 ng/mL. Lewis-Y-specific human T cells were generated by genetic modification with a chimeric receptor encoding a single-chain humanized antibody linked to the T-cell signaling molecules, T-cell receptor-zeta, and CD28. T cells responded against the Lewis-Y antigen by cytokine secretion and cytolysis in response to tumor cells. Importantly, the T-cell response was not inhibited by patient serum containing soluble Lewis-Y. This study demonstrates that Lewis-Y is expressed on a large number of tumors and Lewis-Y-specific T cells can retain antitumor function in the presence of patient serum, indicating that this antigen is a suitable target for this form of therapy.
authors.affiliation: Cancer Immunology Research Program, Peter MacCallum Cancer Centre, St Andrews Place, Melbourne, Victoria 3002, Australia.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: William K
authors.initials: WK
authors.lastname: Murray
authors.forename: Melanie
authors.initials: M
authors.lastname: Trivett
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.forename: David
authors.initials: D
authors.lastname: Ball
authors.forename: Michael
authors.initials: M
authors.lastname: Michael
authors.forename: Angela
authors.initials: A
authors.lastname: Burman
authors.forename: Preethi
authors.initials: P
authors.lastname: Mayura-Guru
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Stefan
authors.initials: S
authors.lastname: Peinert
authors.forename: Dirk
authors.initials: D
authors.lastname: Hönemann
authors.forename: H
authors.initials: H
authors.lastname: Miles Prince
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
mesh_terms: D000951:Antigens, Neoplasm / Q000097:blood / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007983:Lewis Blood Group Antigens / Q000097:blood / Q000235:genetics / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D007983:Lewis Blood Group Antigens; C094162:Lewis Y antigen; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma