title: High-avidity cytotoxic T lymphocytes specific for a new PRAME-derived peptide can target leukemic and leukemic-precursor cells.
abstract: The cancer testis antigen (CTA) preferentially expressed antigen of melanoma (PRAME) is overexpressed by many hematologic malignancies, but is absent on normal tissues, including hematopoietic progenitor cells, and may therefore be an appropriate candidate for T cell-mediated immunotherapy. Because it is likely that an effective antitumor response will require high-avidity, PRAME-specific cytotoxic T lymphocytes (CTLs), we attempted to generate such CTLs using professional and artificial antigen-presenting cells loaded with a peptide library spanning the entire PRAME protein and consisting of 125 synthetic pentadecapeptides overlapping by 11 amino acids. We successfully generated polyclonal, PRAME-specific CTL lines and elicited high-avidity CTLs, with a high proportion of cells recognizing a previously uninvestigated HLA-A*02-restricted epitope, P435-9mer (NLTHVLYPV). These PRAME-CTLs could be generated both from normal donors and from subjects with PRAME(+) hematologic malignancies. The cytotoxic activity of our PRAME-specific CTLs was directed not only against leukemic blasts, but also against leukemic progenitor cells as assessed by colony-forming-inhibition assays, which have been implicated in leukemia relapse. These PRAME-directed CTLs did not affect normal hematopoietic progenitors, indicating that this approach may be of value for immunotherapy of PRAME(+) hematologic malignancies.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Concetta
authors.initials: C
authors.lastname: Quintarelli
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: Sayyeda T
authors.initials: ST
authors.lastname: Hasan
authors.forename: Biagio
authors.initials: B
authors.lastname: De Angelis
authors.forename: Valentina
authors.initials: V
authors.lastname: Hoyos
authors.forename: Santa
authors.initials: S
authors.lastname: Errichiello
authors.forename: Martha
authors.initials: M
authors.lastname: Mims
authors.forename: Luigia
authors.initials: L
authors.lastname: Luciano
authors.forename: Jessica
authors.initials: J
authors.lastname: Shafer
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001782:Blood Donors; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; C404944:PRAME protein, human; D010446:Peptide Fragments