title: A novel murine T-cell receptor targeting NY-ESO-1.
abstract: Cancer testis antigens, such as NY-ESO-1, are expressed in a variety of prevalent tumors and represent potential targets for T-cell receptor (TCR) gene therapy. DNA encoding a murine anti-NY-ESO-1 TCR gene (mTCR) was isolated from immunized HLA-A*0201 transgenic mice and inserted into a γ-retroviral vector. Two mTCR vectors were produced and used to transduce human PBL. Transduced cells were cocultured with tumor target cell lines and T2 cells pulsed with the NY-ESO-1 peptide, and assayed for cytokine release and cell lysis activity. The most active TCR construct was selected for production of a master cell bank for clinical use. mTCR-transduced PBL maintained TCR expression in short-term and long-term culture, ranging from 50% to 90% efficiency 7-11 days after stimulation and 46%-82% 10-20 days after restimulation. High levels of interferon-γ secretion were observed (1000-12000 pg/mL), in tumor coculture assays and recognition of peptide-pulsed cells was observed at 0.1 ng/mL, suggesting that the new mTCR had high avidity for antigen recognition. mTCR-transduced T cells also specifically lysed human tumor targets. In all assays, the mTCR was equivalent or better than the comparable human TCR. As the functional activity of TCR-transduced cells may be affected by the formation of mixed dimers, mTCRs, which are less likely to form mixed dimers with endogenous hTCRs, may be more effective in vivo. This new mTCR targeted to NY-ESO-1 represents a novel potential therapeutic option for adoptive cell-transfer therapy for a variety of malignancies.
authors.affiliation: Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Shannon F
authors.initials: SF
authors.lastname: Rosati
authors.forename: Maria R
authors.initials: MR
authors.lastname: Parkhurst
authors.forename: Young
authors.initials: Y
authors.lastname: Hong
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zheng
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.forename: Mahadev
authors.initials: M
authors.lastname: Rao
authors.forename: Daniel
authors.initials: D
authors.lastname: Abate-Daga
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Beard
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Mary A
authors.initials: MA
authors.lastname: Black
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.forename: David A
authors.initials: DA
authors.lastname: Schrump
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013154:Spleen / Q000166:cytology
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell