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Berlin Brandenburg

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  • 1
    Article
    Article
    Chimeric antigen receptor‐engineered cytokine‐induced killer cells overcome treatment resistance of pre‐B‐cell acute lymphoblastic leukemia and enhance survival (2016)
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    In: International Journal of Cancer, 15 October 2016, Vol.139(8), pp.1799-1809
    Description: Pre‐emptive cancer immunotherapy by donor lymphocyte infusion (DLI) using cytokine‐induced killer (CIK) cells may be beneficial to prevent relapse with a reduced risk of causing graft‐‐host‐disease. CIK cells are a heterogeneous effector cell population including T cells (CD3 CD56), natural killer (NK) cells (CD3CD56) and natural killer T (T‐NK) cells (CD3 CD56) that exhibit non‐major histocompatibility complex (MHC)‐restricted cytotoxicity and are generated by expansion of peripheral blood mononuclear cells in the presence of interferon (IFN)‐γ, anti‐CD3 antibody, interleukin‐2 (IL‐2) and interleukin‐15 (IL‐15). To facilitate selective target‐cell recognition and enhance specific cytotoxicity against B‐cell acute lymphoblastic leukemia (B‐ALL), we transduced CIK cells with a lentiviral vector encoding a chimeric antigen receptor (CAR) that carries a composite CD28‐CD3ζ domain for signaling and a CD19‐specific scFv antibody fragment for cell binding (CAR 63.28.z). analysis revealed high and specific cell killing activity of CD19‐targeted CIK/63.28.z cells against otherwise CIK‐resistant cancer cell lines and primary B‐ALL blasts, which was dependent on CD19 expression and CAR signaling. In a xenograft model in immunodeficient mice, treatment with CIK/63.28.z cells in contrast to therapy with unmodified CIK cells resulted in complete and durable molecular remissions of established primary pre‐B‐ALL. Our results demonstrate potent antileukemic activity of CAR‐engineered CIK cells and , and suggest this strategy as a promising approach for adoptive immunotherapy of refractory pre‐B‐ALL. What's new? Cytokine‐induced killer (CIK) cells are used in pre‐emptive immunotherapy for high‐risk cancer patients. In this study, the authors asked whether the cytotoxicity of CIK cells could be enhanced against B‐ALL. They engineered CIK cells to target a B‐cell‐specific antigen (CD19) by inserting a vector encoding a chimeric antigen receptor (CAR). Compared to controls, the targeted CIK cells were highly cytotoxic , and they also induced durable remissions in a mouse model of human B‐ALL. CAR‐engineered CIK cells may thus be a promising approach for immunotherapy of refractory leukemias.
    Keywords: Adoptive Immunotherapy ; B‐All ; Cytokine‐Induced Killer Cells ; Chimeric Antigen Receptor ; Cd19
    ISSN: 0020-7136
    E-ISSN: 1097-0215
    DOI: 10.1002/ijc.30217
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  • 2
    Article
    Article
    Highlights of the Third International Conference on Immunotherapy in Pediatric Oncology (2013)
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    Language: English
    In: Pediatric Hematology and Oncology, 01 August 2013, Vol.30(5), pp.349-366
    Description: The third International Conference on Immunotherapy in Pediatric Oncology was held in Frankfurt/Main, Germany, October 1-2, 2012. Major topics of the conference included (i) cellular therapies using antigen-specific and gene-modified T cells...
    Keywords: Adcc ; Antibody-Based Immunotherapy ; Car ; Chimeric Antigen Receptor ; Cik ; Cytokine-Induced Killer Cells ; Hematopoietic Stem Cell Transplantation ; Hsct ; Immunotherapy ; Natural Killer Cells Nk ; Oncology ; Medicine
    ISSN: 0888-0018
    E-ISSN: 1521-0669
    DOI: 10.3109/08880018.2013.802106
    URL: View record in Taylor & Francis (Access to full text may be restricted)
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  • 3
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    Article
    Epstein-Barr virus–specific cytokine-induced killer cells for treatment of Epstein-Barr virus–related malignant lymphoma (2018)
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    Language: English
    In: Cytotherapy, June 2018, Vol.20(6), pp.839-850
    Description: Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context. CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities. Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity. The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.
    Keywords: Cytokine-Induced Killer Cells ; Cytotoxic T Cells ; Epstein-Barr Virus ; Immunotherapy ; Lymphoma ; Post-Transplantation Lymphoproliferative Disease ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1465-3249
    E-ISSN: 1477-2566
    DOI: 10.1016/j.jcyt.2018.04.005
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  • 4
    Article
    Article
    In-vitro influence of mycophenolate mofetil (MMF) and Ciclosporin A (CsA) on cytokine induced killer (CIK) cell immunotherapy (2016)
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    Language: English
    In: Journal of translational medicine, 13 September 2016, Vol.14, pp.264
    Description: Cytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue. CIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels. Short-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3(+)CD56(+) cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562. Our data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary.
    Keywords: Allogeneic Stem Cell Transplantation ; Cik Cells ; Immunosuppressive Therapy ; Immunotherapy ; Mmf ; MPA ; Immunotherapy ; Cyclosporine -- Pharmacology ; Cytokine-Induced Killer Cells -- Immunology ; Mycophenolic Acid -- Pharmacology
    E-ISSN: 1479-5876
    DOI: 10.1186/s12967-016-1024-4
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  • 5
    Article
    Article
    Generation and characterization of ErbB2-CAR-engineered cytokine-induced killer cells for the treatment of high-risk soft tissue sarcoma in children (2017)
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    Language: English
    In: Oncotarget, 12 September 2017, Vol.8(39), pp.66137-66153
    Description: Pediatric patients with recurrent, refractory or advanced soft tissue sarcoma (STS) who are simultaneously showing signs of cumulative treatment toxicity are in need of novel therapies. In this preclinical analysis, we identified ErbB2 as a targetable antigen on STS cells and used cytokine-induced killer (CIK) cells transduced with the lentiviral 2-generation chimeric antigen receptor (CAR) vector pS-5.28.z-IEW to target ErbB2-positive tumors. Solely CIK cell subsets with the CD3 T cell phenotype showed up to 85% cell surface expression of the respective CAR. A comparison of wildtype (WT), mock-vector and ErbB2-CAR-CIK cells showed, that engineered cells exhibited diminished expansion, retained WT CIK cell phenotype with higher percentages of differentiated effector memory/effector cells. Activating natural killer (NK) cell receptor NKG2D-restricted target cell recognition and killing of WT and ErbB2-CAR-CIK cells was maintained against ErbB2-negative tumors, while ErbB2-CAR-CIK cells demonstrated significantly increased cytotoxicity against ErbB2-positive targets, including primary tumors. ErbB2-CAR- but not WT CIK cells proliferated, infiltrated and efficiently lysed tumor cell monolayers as well as 3D tumor spheroids. Here, we demonstrate a potential cell therapeutic approach using ErbB2-CAR-CIK cells for the recognition and elimination of tumor cells expressing ErbB2, which we identified as a targetable antigen on high-risk STS cells.
    Keywords: Cell Therapy ; Chimeric Antigen Receptor ; Cytokine-Induced Killer Cells ; Pediatric Cancer ; Soft Tissue Sarcoma
    E-ISSN: 1949-2553
    DOI: 10.18632/oncotarget.19821
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  • 6
    Article
    Article
    Abstract A164: Genetically modified cytokine-induced killer (CIK) cells for targeted cancer therapy (2016)
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    Language: English
    In: Cancer Immunology Research, 01/2016, Vol.4(1 Supplement), pp.A164-A164
    ISSN: 2326-6066
    E-ISSN: 2326-6074
    DOI: 10.1158/2326-6074.CRICIMTEATIAACR15-A164
    Source: CrossRef
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  • 7
    Article
    Article
    Cytomegalovirus-specific cytokine-induced killer cells: concurrent targeting of leukemia and cytomegalovirus (2015)
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    Language: English
    In: Cytotherapy, August 2015, Vol.17(8), pp.1139-1151
    Description: 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. CIK cells expanded in the presence of interferon-γ, IL-2, IL-15 and anti-CD3 antibody were pulsed once with CMVpp65 peptide pool. CMV-specific CIK (CIK ) 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. We demonstrated that among CIK cells generated from CMV-seropositive donors, a single stimulation with CMVpp65 protein co-expanded cytotoxic CMV-specific cells without sacrificing anti-tumor reactivity. Cells generated in this fashion lysed CMVpp65-loaded target cells and CMV-infected fibroblasts but also leukemic cells. Meanwhile, the alloreactive potential of CIK cells remained low. Interestingly, CMV reactivity was TCR-mediated and CMV-specific cells could be found in CD3 CD8 CD56 cytotoxic T-cell subpopulations. We provide an efficient method to generate CIK 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.
    Keywords: Cik Cells ; Cmv ; Cytotoxicity ; Immunotherapy ; Leukemia ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1465-3249
    E-ISSN: 1477-2566
    DOI: 10.1016/j.jcyt.2015.04.011
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  • 8
    Article
    Article
    Cytotoxic potential of IL‐15‐activated cytokine‐induced killer cells against human neuroblastoma cells (2016)
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    In: Pediatric Blood & Cancer, December 2016, Vol.63(12), pp.2230-2239
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/pbc.26147/abstract Byline: Claudia Cappel, Sabine Huenecke, Anica Suemmerer, Stephanie Erben, Eva Rettinger, Verena Pfirrmann, Annekathrin Heinze, Olga Zimmermann, Thomas Klingebiel, Evelyn Ullrich, Peter Bader, Melanie Bremm Keywords: CIK (cytokine-induced killer) cells; immunotherapy; neuroblastoma Abstract Background Neuroblastoma (NB) is the most common solid extracranial tumor in childhood. Despite advances in therapy, the prognosis is poor and optimized therapies are urgently needed. Therefore, we investigated the antitumor potential of interleukin-15 (IL-15)-activated cytokine-induced killer (CIK) cells against different NB cell lines. Procedure CIK cells were generated from peripheral blood mononuclear cells by the stimulation with interferon-[gamma] (IFN-[gamma]), IL-2, OKT-3 and IL-15 over a period of 10-12 days. The cytotoxic activity against NB cells was analyzed by nonradioactive Europium release assay before and after blocking of different receptor-ligand interactions relevant in CIK cell-mediated cytotoxicity. Results The final CIK cell products consisted in median of 83% (range: 75.9-91.9%) CD3.sub.+CD56.sub.- T cells, 14% (range: 5.2-20.7%) CD3.sub.+CD56.sub.+ NK-like T cells and 2% (range: 0.9-4.8%) CD3.sub.-CD56.sub.+ NK cells. CIK cells expanded significantly upon ex vivo stimulation with median rates of 22.3-fold for T cells, 58.3-fold for NK-like T cells and 2.5-fold for NK cells. Interestingly, CD25 surface expression increased from less than equal to 1% up to median 79.7%. Cytotoxic activity of CIK cells against NB cells was in median 34.7, 25.9 and 34.8% against the cell lines UKF-NB-3, UKF-NB-4 and SK-N-SH, respectively. In comparison with IL-2-stimulated NK cells, CIK cells showed a significantly higher cytotoxicity. Antibody-mediated blocking of the receptors NKG2D, TRAIL, FasL, DNAM-1, NKp30 and lymphocyte function-associated antigen-1 (LFA-1) significantly reduced lytic activity, indicating that diverse cytotoxic mechanisms might be involved in CIK cell-mediated NB killing. Conclusions Unlike the mechanism reported in other malignancies, NKG2D-mediated cytotoxicity does not constitute the major killing mechanism of CIK cells against NB. Article Note: Claudia Cappel and Sabine Huenecke contributed equally to the manuscript.
    Keywords: Cik Cytokine‐Induced Killer Cells ; Immunotherapy ; Neuroblastoma
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    DOI: 10.1002/pbc.26147
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  • 9
    Article
    Article
    Development of Three Different NK Cell Subpopulations during Immune Reconstitution after Pediatric Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Markers in GvHD and Viral Infections (2017)
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    Language: English
    In: Frontiers in immunology, 2017, Vol.8, pp.109
    Description: Natural killer (NK) cells play an important role following allogeneic hematopoietic stem cell transplantation (HSCT) exerting graft-versus-leukemia/tumor effect and mediating pathogen-specific immunity. Although NK cells are the first donor-derived lymphocytes reconstituting post-HSCT, their distribution of CD56CD16 (CD56), CD56CD16 (CD56), and CD56CD16 (CD56) NK cells is explicitly divergent from healthy adults, but to some extent comparable to the NK cell development in early childhood. The proportion of CD56/CD56/CD56 changed from 15/8/78% in early childhood to 6/4/90% in adults, respectively. Within this study, we first compared the NK cell reconstitution post-HSCT to reference values of NK cell subpopulations of healthy children. Afterward, we investigated the reconstitution of NK cell subpopulations post-HSCT in correlation to acute graft versus host disease (aGvHD) and chronic graft versus host disease (cGvHD) as well as to viral infections. Interestingly, after a HSCT follow-up phase of 12 months, the distribution of NK cell subpopulations largely matched the 50th percentile of the reference range for healthy individuals. Patients suffering from aGvHD and cGvHD showed a delayed reconstitution of NK cells. Remarkably, within the first 2 months post-HSCT, patients suffering from aGvHD had significantly lower levels of CD56 NK cells compared to patients without viral infection or without graft versus host disease (GvHD). Therefore, the amount of CD56 NK cells might serve as an early prognostic factor for GvHD development. Furthermore, a prolonged and elevated peak in CD56 NK cells seemed to be characteristic for the chronification of GvHD. In context of viral infection, a slightly lower CD56 and CD16 receptor expression followed by a considerable reduction in the absolute CD56 NK cell numbers combined with reoccurrence of CD56 NK cells was observed. Our results suggest that a precise analysis of the reconstitution of NK cell subpopulations post-HSCT might indicate the occurrence of undesired events post-HSCT such as severe aGvHD.
    Keywords: Cd16 ; Cd56 ; Nk Cells ; Allogeneic Transplantation ; Children ; Immune Reconstitution ; Reference Values
    ISSN: 1664-3224
    DOI: 10.3389/fimmu.2017.00109
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  • 10
    Article
    Article
    SMAC Mimetic BV6 Enables Sensitization of Resistant Tumor Cells but also Affects Cytokine-Induced Killer (CIK) Cells: A Potential Challenge for Combination Therapy (2014)
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    Language: English
    In: Frontiers in pediatrics, 2014, Vol.2, pp.75
    Description: Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment option for high-risk hematological malignancies, and may also be offered to patients with solid malignancies refractory to conventional therapies. In case of patients' relapse, refractory tumor cells may then be targeted by cellular therapy-based combination strategies. Here, we investigated the potential of small molecule IAP (SMAC mimetic) BV6 in increasing cytokine-induced killer (CIK) cell-mediated cytotoxicity against different tumor targets. Four-hour pre-incubation with 2.5 μMol BV6 moderately enhanced CIK cell-mediated lysis of hematological (H9, THP-1, and Tanoue) and solid malignancies (RH1, RH30, and TE671). However, BV6 also increased apoptosis of non-malignant cells like peripheral blood mononuclear cells and most notably had an inhibitory effect on immune cells potentially limiting their cytotoxic potential. Hence, cytotoxicity increased in a dose-dependent manner when BV6 was removed before CIK cells were added to tumor targets. However, cytotoxic potential was not further increasable by extending BV6 pre-incubation period of target cells from 4 to 12 h. Molecular studies revealed that BV6 sensitization of target cells involved activation of caspases. Here, we provide evidence that SMAC mimetic may sensitize targets cells for CIK cell-induced cell death. However, BV6 also increased apoptosis of non-malignant cells like CIK cells and peripheral mononuclear cells. These findings may therefore be important for cell- and small molecule IAP-based combination therapies of resistant cancers after allogeneic HSCT.
    Keywords: Bv6 ; Cik Cells ; Cellular Therapy ; Leukemia ; Tumors
    ISSN: 2296-2360
    DOI: 10.3389/fped.2014.00075
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