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Berlin Brandenburg

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  • 1
    Language: English
    In: OncoImmunology, 01 August 2013, Vol.2(8)
    Description: Natural killer (NK) cells hold great promise for adoptive cancer immunotherapy. The antitumor activity of NK cells can be enhanced by the transgene driven expression of chimeric antigen receptors that facilitate the selective recognition and killing of malignant cells. Recent data from our...
    Keywords: Chimeric Antigen Receptor ; Granzyme B ; Nk Cells ; Biology
    ISSN: 21624011
    E-ISSN: 2162-402X
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  • 2
    In: International Journal of Cancer, 01 June 2014, Vol.134(11), pp.2547-2559
    Description: Epidermal growth factor receptor (EGFR) plays an important role in essential cellular processes such as proliferation, survival and migration. Aberrant activation of EGFR is frequently found in human cancers of various origins and has been implicated in cancer pathogenesis. The therapeutic antibody cetuximab (Erbitux) inhibits tumor growth by binding to the extracellular domain of EGFR, thereby preventing ligand binding and receptor activation. This activity is shared by the single chain antibody fragment scFv(225) that contains the same antigen binding domain. The unrelated EGFR‐specific antibody fragment scFv(30) binds to the intracellular domain of the receptor and retains antigen binding upon expression as an intrabody in the reducing environment of the cytosol. Here, we used scFv(225) and scFv(30) domains to generate a novel type of bispecific transmembrane antibody termed 225.TM.30, that simultaneously targets intra‐ and extracellular EGFR epitopes. Bispecific 225.TM.30 and related membrane‐anchored monospecific 225.TM and TM.30 proteins carrying extracellular scFv(225) or intracellular scFv(30) antibody fragments linked to a transmembrane domain were expressed in EGFR‐overexpressing tumor cells using a doxycycline‐inducible retroviral system. Induced expression of 225.TM.30 and 225.TM, but not TM.30 reduced EGFR surface levels and ligand‐induced EGFR activation, while all three molecules markedly inhibited tumor cell growth. Co‐localization of 225.TM with EGFR was predominantly found on the cell surface, while interaction with 225.TM.30 and TM.30 proteins resulted in the redistribution of EGFR to perinuclear compartments. Our data demonstrate functionality of this novel type of membrane‐anchored intrabodies in tumor cells and suggest distinct modes of action of mono‐ and bispecific variants. What's new? Intrabodies are antibodies that have been engineered to be expressed within cells, in order to selectively interfere with cellular processes. In this study, the authors designed a bispecific, membrane‐anchored intrabody with domains that interact both with extracellular and intracellular epitopes of EGFR. When it was expressed in EGFR‐dependent tumor cells, EGFR surface levels, ligand‐induced autophosphorylation, and tumor‐cell growth were all reduced, demonstrating functionality of this novel type of intrabody in tumor cells.
    Keywords: Epidermal Growth Factor Receptor ; Erbb ; Intracellular Antibody ; Intrabody
    ISSN: 0020-7136
    E-ISSN: 1097-0215
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  • 3
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(4), p.e61267
    Description: Natural killer (NK) cells are highly specialized effectors of the innate immune system that hold promise for adoptive cancer immunotherapy. Their cell killing activity is primarily mediated by the pro-apoptotic serine protease granzyme B (GrB), which enters targets cells with the help of the pore-forming protein perforin. We investigated expression of a chimeric GrB fusion protein in NK cells as a means to augment their antitumoral activity. For selective targeting to tumor cells, we fused the epidermal growth factor receptor (EGFR) peptide ligand transforming growth factor α (TGFα) to human pre-pro-GrB. Established human NKL natural killer cells transduced with a lentiviral vector expressed this GrB-TGFα (GrB-T) molecule in amounts comparable to endogenous wildtype GrB. Activation of the genetically modified NK cells by cognate target cells resulted in the release of GrB-T together with endogenous granzymes and perforin, which augmented the effector cells' natural cytotoxicity against NK-sensitive tumor cells. Likewise, GrB-T was released into the extracellular space upon induction of degranulation with PMA and ionomycin. Secreted GrB-T fusion protein displayed specific binding to EGFR-overexpressing tumor cells, enzymatic activity, and selective target cell killing in the presence of an endosomolytic activity. Our data demonstrate that ectopic expression of a targeted GrB fusion protein in NK cells is feasible and can enhance antitumoral activity of the effector cells.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 4
    Language: English
    In: Cancer Research, 04/15/2011, Vol.71(8 Supplement), pp.1808-1808
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 5
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.2808-2808
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2010, Vol.5(12), p.e14404
    Description: BACKGROUND: The apoptosis-inducing serine protease granzyme B (GrB) is an important factor contributing to lysis of target cells by cytotoxic lymphocytes. Expression of enzymatically active GrB in recombinant form is a prerequisite for functional analysis and application of GrB for therapeutic purposes. METHODS AND FINDINGS: We investigated the influence of bacterial maltose-binding protein (MBP) fused to GrB via a synthetic furin recognition motif on the expression of the MBP fusion protein also containing an N-terminal α-factor signal peptide in the yeast Pichia pastoris. MBP markedly enhanced the amount of GrB secreted into culture supernatant, which was not the case when GrB was fused to GST. MBP-GrB fusion protein was cleaved during secretion by an endogenous furin-like proteolytic activity in vivo, liberating enzymatically active GrB without the need of subsequent in vitro processing. Similar results were obtained upon expression of a recombinant fragment of the ErbB2/HER2 receptor protein or GST as MBP fusions. CONCLUSIONS: Our results demonstrate that combination of MBP as a solubility enhancer with specific in vivo cleavage augments secretion of processed and functionally active proteins from yeast. This strategy may be generally applicable to improve folding and increase yields of recombinant proteins.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(8), p.e72756
    Description: Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Cancer Research, 04/15/2013, Vol.73(8 Supplement), pp.3967-3967
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    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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  • 10
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(5)
    Description: Background: Glioblastoma (GBM) is the most common and malignant intracranial tumor in adults and currently incurable. To specifically target natural killer (NK) cell activity to GBM, we employed NK-92/5.28.Z cells that are continuously expanding human NK cells expressing an ErbB2-specific chimeric antigen receptor (CAR). Methods: ErbB2 expression in 56 primary tumors, four primary cell cultures, and seven established cell lines was assessed by immunohistochemistry and flow cytometry. Cell killing activity of NK-92/5.28.Z cells was analyzed in in vitro cytotoxicity assays. In vivo antitumor activity was evaluated in NOD-SCID IL2Ry[[gamma].sup.null] (NSG) mice carrying orthotopic human GBM xenografts (6 to 11 mice per group) and C57BL/6 mice carrying subcutaneous and orthotopic ErbB2-expressing murine GBM tumors (5 to 8 mice per group). Statistical tests were two-sided. Results: We found elevated ErbB2 protein expression in 41% of primary GBM samples and in the majority of GBM cell lines investigated. In in vitro assays, NK-92/5.28.Z in contrast to untargeted NK-92 cells lysed all ErbB2-positive established and primary GBM cells analyzed. Potent in vivo antitumor activity of NK-92/5.28.Z was observed in orthotopic GBM xenograft models in NSG mice, leading to a marked extension of symptom-free survival upon repeated stereotactic injection of CAR NK cells into the tumor area (median survival of 200.5 days upon treatment with NK- 92/5.28.Z vs 73 days upon treatment with parental NK-92 cells, P 〈 .001). In immunocompetent mice, local therapy with NK-92/5.28.Z cells resulted in cures of transplanted syngeneic GBM in four of five mice carrying subcutaneous tumors and five of eight mice carrying intracranial tumors, induction of endogenous antitumor immunity, and long-term protection against tumor rechallenge at distant sites. Conclusions: Our data demonstrate the potential of ErbB2-specific NK-92/5.28.Z cells for adoptive immunotherapy of glioblastoma, justifying evaluation of this approach for the treatment of ErbB2-positive GBM in clinical studies. doi: 10.1093/jnci/djv375
    Keywords: Glioblastomas -- Care And Treatment ; Killer Cells -- Usage ; Killer Cells -- Health Aspects ; Molecular Targeted Therapy -- Methods;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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