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  • 1
    Language: English
    In: Progressive Neuroblastoma, 2015, Vol.20, p.163-177
    Description: Abstract Immunotherapy has emerged as an alternative strategy to treat high-risk neuroblastoma stage IV in addition to surgery and conventional radio- and chemotherapy. Today, most therapy protocols for high-risk neuroblastoma include myeloablative chemotherapy which attempts to eradicate the disease, followed by the infusion of autologous stem cells to repopulate the bone marrow. Especially for patients suffering from a relapse after autologous hematopoietic stem cell transplantation (HSCT), but also for a few patients at the early stage of disease, the transplantation of allogeneic/haploidentical stem cells has been considered. Within the last decade, these transplantation strategies have been combined with adoptive cellular therapies using donor lymphocytes with a special focus on natural killer (NK) cells. However, experience with allogeneic HSCT for neuroblastoma with and without additional cell therapies is rare. In a clinical phase I/II trial including 4 patients diagnosed with neuroblastoma stage IV, the feasibility and efficacy of haploidentical HSCT with the adoptive therapy of highly purified IL-2-activated NK cells has been shown. It is encouraging that 2 out of the 4 patients suffering from high-risk neuroblastoma stage IV are alive and well, with no evidence of disease more than 4.7 years after haploidentical HSCT and additional immunotherapy using IL-2-stimulated donor NK cells. © 2015 S. Karger AG, Basel
    ISBN: 978-3-318-05496-5
    ISSN: 1017-5989
    E-ISSN: 1662-3886
    Source: Karger Book Series
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  • 2
    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
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  • 3
    Language: English
    In: Biology of Blood and Marrow Transplantation, January 2017, Vol.23(1), pp.87-95
    Description: Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.
    Keywords: Allogeneic Hematopoietic Stem Cell Transplantation ; Chimerism ; Minimal Residual Disease ; Pre-Emptive Immunotherapy ; Medicine
    ISSN: 1083-8791
    E-ISSN: 1523-6536
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  • 4
    Language: English
    In: Bone marrow transplantation, July 2018, Vol.53(7), pp.891-894
    Keywords: Hematopoietic Stem Cell Transplantation -- Methods ; Sarcoma -- Therapy ; Transplantation Conditioning -- Methods ; Transplantation, Homologous -- Methods
    ISSN: 02683369
    E-ISSN: 1476-5365
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  • 5
    Language: English
    In: Biology of Blood and Marrow Transplantation, February 2013, Vol.19(2), pp.S242-S242
    Keywords: Medicine
    ISSN: 1083-8791
    E-ISSN: 1523-6536
    Source: ScienceDirect Journals (Elsevier)
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  • 6
    Language: English
    In: Biology of Blood and Marrow Transplantation, February 2014, Vol.20(2), pp.S175-S175
    Keywords: Medicine
    ISSN: 1083-8791
    E-ISSN: 1523-6536
    Source: ScienceDirect Journals (Elsevier)
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  • 7
    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
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  • 8
    Language: English
    In: Cytotherapy, June 2014, Vol.16(6), pp.835-844
    Description: 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. 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. 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 . 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.
    Keywords: Anti-Tumor Potential ; Cytokine-Induced Killer Cells ; Mouse Model ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1465-3249
    E-ISSN: 1477-2566
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  • 9
    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
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  • 10
    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
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