title: Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors.
abstract: NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157-165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1157-165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1157-165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.
authors.affiliation: Haematology Section, Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Adams
authors.forename: Namir J
authors.initials: NJ
authors.lastname: Hassan
authors.forename: Akhil
authors.initials: A
authors.lastname: Kotian
authors.forename: Nikolai M
authors.initials: NM
authors.lastname: Lissin
authors.forename: Malkit
authors.initials: M
authors.lastname: Sami
authors.forename: Maja
authors.initials: M
authors.lastname: Mujić
authors.forename: Tereza
authors.initials: T
authors.lastname: Osdal
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Deborah
authors.initials: D
authors.lastname: Baker
authors.forename: Alex S
authors.initials: AS
authors.lastname: Powlesland
authors.forename: Milos
authors.initials: M
authors.lastname: Aleksic
authors.forename: Annelise
authors.initials: A
authors.lastname: Vuidepot
authors.forename: Olivier
authors.initials: O
authors.lastname: Morteau
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Sutton
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ashfield
authors.forename: Bent K
authors.initials: BK
authors.lastname: Jakobsen
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism; D011897:Random Allocation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D017252:CD3 Complex; C104948:CTAG1B protein, human; C510162:CTAG2 protein, human; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D007128:Immunoglobulin Fragments; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins