title: Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy.
abstract: OBJECTIVE
  Although modern cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 80%, the outlook remains poor in patients with high-risk disease and those who relapse, especially when allogeneic hematopoietic stem cell transplantation is not feasible. Strategies to improve outcome and prevent relapse are therefore required. Immunotherapy with antigen-specific T cells can have antileukemic activity without the toxicities seen with intensive chemotherapy, and therefore represents an attractive strategy to improve the outcome of high-risk patients with ALL. We explored the feasibility of generating tumor antigen-specific T cells ex vivo from the peripheral blood of 50 patients with ALL [26 National Cancer Institute (NCI) high-risk and 24 standard-risk] receiving maintenance therapy.
  
  
  METHODS
  Peripheral blood mononuclear cells were stimulated with autologous dendritic cells pulsed with complete peptide libraries of WT1, Survivin, MAGE-A3, and PRAME, antigens frequently expressed on ALL blasts.
  
  
  RESULTS
  T-cell lines were successfully expanded from all patients, despite low lymphocyte counts and irrespective of NCI risk group. Antigen-specificity was observed in more than 50% of patients after the initial stimulation and increased to more than 90% after three stimulations as assessed in IFN-γ-enzyme-linked immunospot (ELISpot) and (51)Cr-release assays. Moreover, tumor-specific responses were observed by reduction of autologous leukemia blasts in short- and long-term coculture experiments.
  
  
  CONCLUSIONS
  This study supports the use of immunotherapy with adoptively transferred autologous tumor antigen-specific T cells to prevent relapse and improve the prognosis of patients with high-risk ALL.
authors.affiliation: Authors' Affiliations: Center for Cell and Gene Therapy, Departments of Pediatrics, Medicine, and Immunology, Baylor College of Medicine; The Methodist Hospital; Texas Children's Hospital; Texas Children's Cancer Center, Houston, Texas; and Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Weber
authors.forename: Ignazio
authors.initials: I
authors.lastname: Caruana
authors.forename: Rayne H
authors.initials: RH
authors.lastname: Rouce
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gerdemann
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
authors.forename: Karen R
authors.initials: KR
authors.lastname: Rabin
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002648:Child; D003114:Colony-Forming Units Assay; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005240:Feasibility Studies; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D011379:Prognosis; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D025721:WT1 Proteins / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; C404944:PRAME protein, human; D010446:Peptide Fragments; D000077022:Survivin; D025721:WT1 Proteins; D007371:Interferon-gamma