title: Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor.
abstract: Adoptive immunotherapy of cancer requires the generation of large numbers of tumor antigen-reactive T cells for transfer into cancer patients. Genes encoding tumor antigen-specific T-cell receptors can be introduced into primary human T cells by retroviral mediated gene transfer as a potential method of providing any patient with a source of autologous tumor-reactive T cells. A T-cell receptor-specific for a class I MHC (HLA-A2)-restricted epitope of the melanoma antigen tyrosinase was isolated from a CD4(+) tumor-infiltrating lymphocyte (TIL 1383I) and introduced into normal human peripheral blood lymphocytes by retroviral transduction. T-cell receptor-transduced T cells secreted various cytokines when cocultured with tyrosinase peptide-loaded antigen-presenting cells as well as melanoma cells in an HLA-A2-restricted manner, and could also lyse target cells. Furthermore, T-cell clones isolated from these cultures showed both CD8(+) and CD4(+) transduced T cells could recognize HLA-A2(+) melanoma cells, giving us the possibility of engineering class I MHC-restricted effector and T helper cells against melanoma. The ability to confer class I MHC-restricted tumor cell recognition to CD4(+) T cells makes the TIL 1383I TCR an attractive candidate for T-cell receptor gene transfer-based immunotherapy.
authors.affiliation: Department of Surgery and Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Roszkowski
authors.forename: Gretchen E
authors.initials: GE
authors.lastname: Lyons
authors.forename: W Martin
authors.initials: WM
authors.lastname: Kast
authors.forename: Cassian
authors.initials: C
authors.lastname: Yee
authors.forename: Koen
authors.initials: K
authors.lastname: Van Besien
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D014442:Monophenol Monooxygenase / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D014442:Monophenol Monooxygenase