title: Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.
abstract: Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: G
authors.initials: G
authors.lastname: Weber
authors.forename: U
authors.initials: U
authors.lastname: Gerdemann
authors.forename: I
authors.initials: I
authors.lastname: Caruana
authors.forename: B
authors.initials: B
authors.lastname: Savoldo
authors.forename: N F
authors.initials: NF
authors.lastname: Hensel
authors.forename: K R
authors.initials: KR
authors.lastname: Rabin
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: J J
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: A M
authors.initials: AM
authors.lastname: Leen
authors.forename: A J
authors.initials: AJ
authors.lastname: Barrett
authors.forename: C M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D018604:Epitope Mapping; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006650:Histocompatibility Testing; D006801:Humans; D016130:Immunophenotyping; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy*; D019272:Leukocyte Elastase / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D053146:Myeloblastin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012008:Recurrence; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D025721:WT1 Proteins / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D025721:WT1 Proteins; C028388:thymus-leukemia antigens; D019272:Leukocyte Elastase; D053146:Myeloblastin