title: Generation of autologous cytotoxic and helper T-cell responses against the B-cell leukemia-associated antigen HB-1: relevance for precursor B-ALL-specific immunotherapy.
abstract: Tumor relapses in patients with precursor B-cell acute lymphoblastic leukemia (BALL) occur frequently after primary treatment. Therefore, development of additional treatment modalities to eliminate residual tumor cells is needed. Active immunotherapy using dendritic cells (DCs) loaded with tumor-associated antigens is a promising approach to induce specific T-cell immunity in patients with cancer. In previous studies, we described HB-1 as a B-cell lineage-specific antigen that is recognized by donor-derived cytotoxic T lymphocytes (CTLs) on allogeneic B-ALL tumor cells. Here, we investigated the potential use of the HB-1 antigen as an autologous T-cell vaccine target. To determine whether HB-1-specific CTL precursors are present within the T-cell repertoire, we induced expansion of CD8+ T cells using mature monocyte-derived DCs pulsed with the previously identified HB-1.B44 antigenic peptide. In 6 of 8 donors, CD8+ CTL lines have been generated that exert cytotoxicity against target cells exogenously pulsed with peptide or endogenously expressing the HB-1 antigen. From one of these HB-1-specific T-cell lines, we isolated a CD8+ CTL that produces interferon-gamma on stimulation with B-ALL tumor cells. Interestingly, the HB-1 antigen also induced CD4+ T-helper responses on activation with protein-loaded mature monocyte-derived DCs. We identified 2 novel epitopes recognized in the context of HLA-DR4 and HLA-DR11 with the use of HB-1-specific CD4+ T-cell clones generated from different donors. These present data, that HB-1 induces both helper and cytotoxic T-cell responses, indicate that the HB-1 antigen is a candidate target to induce T-cell-mediated antitumor immunity in patients.
authors.affiliation: Central Hematology Laboratory and Department of Hematology, University Medical Center St Radboud, 6500 HB Nijmegen, The Netherlands.
authors.forename: Bjorn
authors.initials: B
authors.lastname: de Rijke
authors.forename: Hanny
authors.initials: H
authors.lastname: Fredrix
authors.forename: Agnes
authors.initials: A
authors.lastname: Zoetbrood
authors.forename: Frank
authors.initials: F
authors.lastname: Scherpen
authors.forename: Henry
authors.initials: H
authors.lastname: Witteveen
authors.forename: Theo
authors.initials: T
authors.lastname: de Witte
authors.forename: Elly
authors.initials: E
authors.lastname: van de Wiel-Van Kemenade
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis; D002857:Chromium / Q000378:metabolism; D003713:Dendritic Cells; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000378:metabolism; D015235:HLA-B Antigens / Q000378:metabolism*; D006684:HLA-DR Antigens / Q000378:metabolism; D059810:HLA-DR Serological Subtypes; D015804:HLA-DR4 Antigen / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D015448:Leukemia, B-Cell / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D015778:Minor Histocompatibility Antigens; D009000:Monocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D013601:T-Lymphocytes / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*
chemical_list: D016827:CD8 Antigens; D000939:Epitopes; D015235:HLA-B Antigens; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C080766:HLA-DR11 antigen; D015804:HLA-DR4 Antigen; C117270:HMHB1 protein, human; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D002857:Chromium; D007371:Interferon-gamma