The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells.

BACKGROUND AIMS Cytokine-induced killer (CIK) cells may serve as an alternative approach to adoptive donor lymphocyte infusions (DLI) for patients with acute leukemia relapsing after haplo-identical hematopoietic stem cell transplantation (HSCT). We investigated the feasibility of enhancing CIK cell-mediated cytotoxicity by interleukin (IL)-15 against acute myeloid and lymphoblastic leukemia/lymphoma cells. METHODS CIK cells were activated using IL-2 (CIK(IL-2)) or IL-15 (CIK(IL-15)) and phenotypically analyzed by fluorescence-activated cell sorting (FACS). Cytotoxic potential was measured by europium release assay. RESULTS CIK(IL-2) cells showed potent cytotoxicity against the T-lymphoma cell line H9, T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT-4 and subtype M4 acute myeloid leukemia (AML) cell line THP-1, but low cytotoxicity against the precursor B (pB)-cell ALL cell line Tanoue. IL-15 stimulation resulted in a significant enhancement of CIK cell-mediated cytotoxicity against acute lymphoblastic leukemia/lymphoma cell lines as well as against primary acute myeloid and defined lymphoblastic leukemia cells. However, the alloreactive potential of CIK(IL-15) cells remained low. Further analysis of CIK(IL-15) cells demonstrated that the NKG2D receptor is apparently involved in the recognition of target cells whereas killer-cell immunoglobulin-like receptor (KIR)-HLA mismatches contributed to a lesser extent to the CIK(IL-15) cell-mediated cytotoxicity. In this context, CD3 (+) CD8 (+) CD25 (+) CD56(-) CIK(IL-15) cell subpopulations were more effective in the lysis of AML cells, in contrast with CD56 (+) CIK(IL-15) cells, which showed the highest cytotoxic potential against ALL cells. CONCLUSIONS This study provides the first evidence that CIK(IL-15) cells may offer a therapeutic option for patients with refractory or relapsed leukemia following haplo-identical HSCT.

[1]  D. Messmer,et al.  Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC) , 2011, Journal of Cancer Research and Clinical Oncology.

[2]  S. Rutella,et al.  Thymoglobulin, interferon-γ and interleukin-2 efficiently expand cytokine-induced killer (CIK) cells in clinical-grade cultures , 2010, Journal of Translational Medicine.

[3]  A. Lawson,et al.  Cytokine-induced killer cells for cell therapy of acute myeloid leukemia: improvement of their immune activity by expression of CD33-specific chimeric receptors , 2010, Haematologica.

[4]  S. Klöss,et al.  Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation , 2010, Haematologica.

[5]  Yang Li,et al.  Optimized protocols for generation of cord blood-derived cytokine-induced killer/natural killer cells. , 2010, Anticancer research.

[6]  Wei Kong,et al.  Cytotoxic effect of trans-cinnamaldehyde on human leukemia K562 cells , 2010, Acta Pharmacologica Sinica.

[7]  C. Aspord,et al.  Exploration of the Lysis Mechanisms of Leukaemic Blasts by Chimaeric T-Cells , 2010, Journal of biomedicine & biotechnology.

[8]  K. Hui,et al.  Cytokine-Induced NK-Like T Cells: From Bench to Bedside , 2010, Journal of biomedicine & biotechnology.

[9]  R. Handgretinger,et al.  Identification and selective depletion of alloreactive T-cells for adoptive immunotherapy. , 2010, Laboratory hematology : official publication of the International Society for Laboratory Hematology.

[10]  J. Passweg,et al.  IL-2−driven Regulation of NK Cell Receptors With Regard to the Distribution of CD16+ and CD16− Subpopulations and In Vivo Influence After Haploidentical NK Cell Infusion , 2010, Journal of immunotherapy.

[11]  W. Piacibello,et al.  Cytokine induced killer cells as adoptive immunotherapy strategy to augment graft versus tumor after hematopoietic cell transplantation , 2009, Expert opinion on biological therapy.

[12]  M. Introna,et al.  Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. , 2009, Experimental hematology.

[13]  J. Falkenburg,et al.  Long-term culture of primary human lymphoblastic leukemia cells in the absence of serum or hematopoietic growth factors. , 2009, Experimental hematology.

[14]  L. H. Ng,et al.  Characterization of the recognition and functional heterogeneity exhibited by cytokine‐induced killer cell subsets against acute myeloid leukaemia target cell , 2009, Immunology.

[15]  A. Fauci,et al.  The Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Induce the Expression of Programmed Death-1 and Its Ligands , 2008, The Journal of Immunology.

[16]  M. Aglietta,et al.  Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. , 2008, International immunology.

[17]  Hui Li,et al.  CD4+T cells in CIKs (CD4+ CIKs) reversed resistance to fas-mediated apoptosis through CD40/CD40L ligation rather than IFN-gamma stimulation. , 2008, Cancer biotherapy & radiopharmaceuticals.

[18]  R. Sun,et al.  Different roles of IL-15 from IL-2 in differentiation and activation of human CD3+CD56+ NKT-like cells from cord blood in long term culture. , 2008, International immunopharmacology.

[19]  T. Barbui,et al.  Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. , 2007, Haematologica.

[20]  A. Biondi,et al.  Characterization of in vitro migratory properties of anti-CD19 chimeric receptor-redirected CIK cells for their potential use in B-ALL immunotherapy. , 2006, Experimental hematology.

[21]  J. Ritz,et al.  IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. , 2006, Blood.

[22]  D. Yan,et al.  Effect of interleukin-15 on alloreactivity in umbilical cord blood. , 2006, Transplant immunology.

[23]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[24]  M. Horowitz,et al.  Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. , 2005, Blood.

[25]  S. Savaşan,et al.  Combinational IL-2/IL-15 induction does not further enhance IL-15-induced lymphokine-activated killer cell cytotoxicity against human leukemia/lymphoma cells. , 2005, Clinical immunology.

[26]  C. Ziske,et al.  Transfection of human monocyte‐derived dendritic cells with CpG oligonucleotides , 2005, Immunology and cell biology.

[27]  Junya Chen,et al.  [Effect of dendritic cells co-cultured with cytokine induced killer cells on cytotoxicity against drug resistant K562 cells]. , 2005, Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi.

[28]  M. Caligiuri,et al.  Donor-derived IL-15 is critical for acute allogeneic graft-versus-host disease. , 2005, Blood.

[29]  W. Leonard,et al.  Cytokines and immunodeficiency diseases: critical roles of the γc‐dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways , 2004, Immunological reviews.

[30]  K. Dietz,et al.  Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  Robert S Negrin,et al.  Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. , 2004, Blood.

[32]  E. Seifried,et al.  Assessment of killer cell immunoglobulinlike receptor expression and corresponding HLA class I phenotypes demonstrates heterogenous KIR expression independent of anticipated HLA class I ligands. , 2003, Human immunology.

[33]  R. Negrin,et al.  Studies of ex Vivo Activated and Expanded CD8+ NK-T Cells in Humans and Mice , 2002, Journal of Clinical Immunology.

[34]  T. Waldmann.  The IL-2/IL-15 Receptor Systems: Targets for Immunotherapy , 2002, Journal of Clinical Immunology.

[35]  K. Hui,et al.  Generation of cytokine‐induced killer cells from leukaemic samples with in vitro cytotoxicity against autologous 
and allogeneic leukaemic blasts , 2002, British journal of haematology.

[36]  S. Marx,et al.  Bench to bedside: the development of rapamycin and its application to stent restenosis. , 2001, Circulation.

[37]  R. Negrin,et al.  Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. , 2001, Blood.

[38]  Y. Tanaka,et al.  TRAIL expression by activated human CD4(+)V alpha 24NKT cells induces in vitro and in vivo apoptosis of human acute myeloid leukemia cells. , 2001, Blood.

[39]  P. Marrack,et al.  Control of homeostasis of CD8+ memory T cells by opposing cytokines. , 2000, Science.

[40]  M. Sykes,et al.  Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. , 1998, The Journal of clinical investigation.

[41]  R. Negrin,et al.  Expansion of Philadelphia chromosome-negative CD3(+)CD56(+) cytotoxic cells from chronic myeloid leukemia patients: in vitro and in vivo efficacy in severe combined immunodeficiency disease mice. , 1998, Blood.

[42]  J. Johnston,et al.  Signaling by IL‐2 and related cytokines: JAKs, STATs, and relationship to immunodeficiency , 1996, Journal of leukocyte biology.

[43]  J. D. Di Santo,et al.  Common cytokine receptor gamma chain (gamma c)-dependent cytokines: understanding in vivo functions by gene targeting. , 1995, Immunological reviews.

[44]  R. Negrin,et al.  A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. , 1994, Journal of immunology.

[45]  I. Weissman,et al.  Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. , 1993, Experimental hematology.

[46]  H. Young,et al.  Comparative studies of CD3- and CD3+ CD56+ cells: examination of morphology, functions, T cell receptor rearrangement, and pore-forming protein expression. , 1991, Cellular immunology.

[47]  I. Weissman,et al.  Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity , 1991, The Journal of experimental medicine.

[48]  C. Klein,et al.  Enhanced killing of human B-cell lymphoma targets by combined use of cytokine-induced killer cell (CIK) cultures and anti-CD20 antibodies. , 2011, Blood.

[49]  M. Caligiuri,et al.  Interleukin-2, interleukin-15, and their roles in human natural killer cells. , 2005, Advances in immunology.

[50]  M. Humphries.  Supplement Review , 2001 .

[51]  D. Huhn,et al.  Expansion of CD3+CD56+ cytotoxic cells from patients with chronic lymphocytic leukemia: in vitro efficacy. , 2000, Haematologica.