title: Cytomegalovirus-specific cytokine-induced killer cells: concurrent targeting of leukemia and cytomegalovirus.
abstract: OBJECTIVE
  Human cytomegalovirus (CMV) infection and reactivation is a leading complication of allogeneic hematopoietic stem cell transplantation (HSCT). In addition to drug treatment, the adoptive transfer of virus-specific T cells to restore cellular immunity has become a standard therapy after allogeneic HSCT. We recently demonstrated potent anti-leukemic activity of interleukin (IL)-15-activated cytokine-induced killer (CIK) cells. With the use of the same expansion protocol, we asked whether concurrent CMV antigen-pulsing might generate CIK cells with anti-leukemic and anti-CMV activity.
  
  
  METHODS
  CIK cells expanded in the presence of interferon-γ, IL-2, IL-15 and anti-CD3 antibody were pulsed once with CMV(pp65) peptide pool. CMV-specific CIK (CIK(pp65)) and conventional CIK cells were phenotypically and functionally characterized according to their cytokine secretion pattern, degranulation capacity and T-cell receptor (TCR)-mediated and NKG2D-mediated cytotoxicity.
  
  
  RESULTS
  We demonstrated that among CIK cells generated from CMV-seropositive donors, a single stimulation with CMV(pp65) protein co-expanded cytotoxic CMV-specific cells without sacrificing anti-tumor reactivity. Cells generated in this fashion lysed CMV(pp65)-loaded target cells and CMV-infected fibroblasts but also leukemic cells. Meanwhile, the alloreactive potential of CIK(pp65) cells remained low. Interestingly, CMV reactivity was TCR-mediated and CMV-specific cells could be found in CD3(+)CD8(+)CD56(+/-) cytotoxic T-cell subpopulations.
  
  
  CONCLUSIONS
  We provide an efficient method to generate CIK(pp65) cells that may represent a useful cell therapy approach for preemptive immunotherapy in patients who have both an apparent risk of CMV and impending leukemic relapse after allogeneic stem cell transplantation.
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany. Electronic address: verena.pfirrmann@kgu.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Pfirrmann
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt/Main, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Oelsner
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rettinger
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Huenecke
authors.affiliation: Institute for Transfusion Medicine and Immunohematology and German Red Cross Blood Donor Service, University Hospital Frankfurt, Goethe University, Baden-Wuerttemberg-Hessen, Frankfurt/Main, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Merker
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt/Main, Germany.
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.affiliation: Institute for Experimental Cancer Research in Pediatrics, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
authors.affiliation: Division of Allergology, Pneumology and Cystic Fibrosis, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schubert
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: Division of Stem Cell Transplantation and Immunology, Department of Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt/Main, Germany. Electronic address: peter.bader@kgu.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
mesh_terms: D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D055612:Cytokine-Induced Killer Cells / Q000166:cytology / Q000637:transplantation*; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000628:therapy* / Q000821:virology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology / Q000628:therapy; D010750:Phosphoproteins / Q000276:immunology; D033581:Stem Cell Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D007371:Interferon-gamma
keywords: CIK cells; CMV; cytotoxicity; immunotherapy; leukemia