title: Immunomagnetic selection or irradiation eliminates alloreactive cells but also reduces anti-tumor potential of cytokine-induced killer cells: implications for unmanipulated cytokine-induced killer cell infusion.
abstract: OBJECTIVE
  Cytokine-induced killer (CIK) cells may offer a novel therapeutic approach for patients with malignancies relapsing after allogeneic stem cell transplantation. Although CIK cells display negligible alloreactivity and cause minimal graft versus-host-disease (GVHD), high CIK cell doses required during relapse may pose a risk for severe GVHD, specifically in the mismatched or haploidentical transplantation setting. Manipulation of CIK cells may reduce risk for GVHD without affecting the anti-tumor potential.
  
  
  METHODS
  In this pre-clinical study, we provide a detailed functional comparison of conventional and irradiated, CD56-enriched or T-cell receptor α/β-depleted CIK cells.
  
  
  RESULTS
  In vitro analysis showed retained anti-leukemic and anti-tumor potential after CIK cell manipulation. Even being sequentially infused into immunodeficient mice grafted with malignant cells, cytotoxic effects were fewest after irradiation but were improved by CD56 enrichment and were best with conventional CIK cells. Hence, considering the proliferative capacity of inoculated malignancies and effector cells, a single dose of conventional CIK cells resulted in prolonged disease-free survival and elimination of rhabdomyosarcoma cells, whereas sequential infusions were needed to achieve comparable results in leukemia-bearing mice. However, this mouse model has limitations: highly effective conventional CIK cells demonstrated both limited xenogenic GVHD and low alloreactive potential in vitro.
  
  
  CONCLUSIONS
  Our study revealed that conventional CIK cells demonstrate no significant alloreactive potential but provide the strongest anti-tumor efficacy compared with manipulated CIK cells. Conventional CIK cells may therefore be tested in high numbers and short-term intervals in patients with impending relapse even after mismatched transplantation.
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany. Electronic address: eva.rettinger@kgu.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Rettinger
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Merker
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Selim
authors.initials: S
authors.lastname: Kuçi
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Willasch
authors.affiliation: Department of Medicine II, Hematology, Oncology, Rheumatology and Infectious Diseases, University Hospital Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany; LOEWE Center for Cell and Gene Therapy, Frankfurt/Main, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ullrich
authors.affiliation: Georg-Speyer-Haus, Institut für Tumorbiologie und experimentelle Therapie Frankfurt/Main, Germany.
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Goethe-University Frankfurt/Main, German Red Cross Blood Donor Service Baden-Württemberg-Hessen, Division for Cell Processing, Frankfurt/Main, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bonig
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.affiliation: University Hospital Frankfurt/Main, Department for Children and Adolescents Medicine, Division of Stem Cell Transplantation and Immunology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
mesh_terms: D000818:Animals; D055612:Cytokine-Induced Killer Cells / Q000166:cytology / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018572:Disease-Free Survival; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D018189:Immunomagnetic Separation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000628:therapy; D033581:Stem Cell Transplantation / Q000379:methods; D014184:Transplantation, Homologous / Q000379:methods*
keywords: anti-tumor potential; cytokine-induced killer cells; mouse model