title: Development of a T cell receptor targeting an HLA-A*0201 restricted epitope from the cancer-testis antigen SSX2 for adoptive immunotherapy of cancer.
abstract: The clinical success of adoptive immunotherapy of cancer relies on the selection of target antigens that are highly expressed in tumor cells but absent in essential normal tissues. A group of genes that encode the cancer/testis or cancer germline antigens have been proposed as ideal targets for immunotherapy due to their high expression in multiple cancer types and their restricted expression in immunoprivileged normal tissues. In the present work we report the isolation and characterization of human T cell receptors (TCRs) with specificity for synovial sarcoma X breakpoint 2 (SSX2), a cancer/testis antigen expressed in melanoma, prostate cancer, lymphoma, multiple myeloma and pancreatic cancer, among other tumors. We isolated seven HLA-A2 restricted T cell receptors from natural T cell clones derived from tumor-infiltrated lymph nodes of two SSX2-seropositive melanoma patients, and selected four TCRs for cloning into retroviral vectors. Peripheral blood lymphocytes (PBL) transduced with three of four SSX2 TCRs showed SSX241-49 (KASEKIFYV) peptide specific reactivity, tumor cell recognition and tetramer binding. One of these, TCR-5, exhibited tetramer binding in both CD4 and CD8 cells and was selected for further studies. Antigen-specific and HLA-A*0201-restricted interferon-γ release, cell lysis and lymphocyte proliferation was observed following culture of TCR engineered human PBL with relevant tumor cell lines. Codon optimization was found to increase TCR-5 expression in transduced T cells, and this construct has been selected for development of clinical grade viral vector producing cells. The tumor-specific pattern of expression of SSX2, along with the potent and selective activity of TCR-5, makes this TCR an attractive candidate for potential TCR gene therapy to treat multiple cancer histologies.
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Abate-Daga
authors.affiliation: Department of Oncology, Ludwig Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Nachimuthu
authors.initials: N
authors.lastname: Chinnasamy
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Feldman
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D013737:Testis / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C093962:synovial sarcoma X breakpoint proteins; D007371:Interferon-gamma