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  • 1
    Online Resource
    Online Resource
    Multivalent Protein‐Loaded pH‐Stable Polymersomes: First Step toward Protein Targeted Therapeutics
    Wiley ; 2021
    In:  Macromolecular Bioscience Vol. 21, No. 10 ( 2021-10)
    Details
    In: Macromolecular Bioscience, Wiley, Vol. 21, No. 10 ( 2021-10)
    Abstract: Synthetic platforms for mimicking artificial organelles or for designing multivalent protein therapeutics for targeting cell surface, extracellular matrix, and tissues are in the focus of this study. Furthermore, the availability of a multi‐functionalized and stimuli‐responsive carrier system is required that can be used for sequential in situ and/or post loading of different proteins combined with post‐functionalization steps. Until now, polymersomes exhibit excellent key characteristics to fulfill those requirements, which allow specific transport of proteins and the integration of proteins in different locations of polymeric vesicles. Herein, different approaches to fabricate multivalent protein‐loaded, pH‐responsive, and pH‐stable polymersomes are shown, where a combination of therapeutic action and targeting can be achieved, by first choosing two model proteins such as human serum albumin and avidin. Validation of the molecular parameters of the multivalent biohybrids is performed by dynamic light scattering, cryo‐TEM, fluorescence spectroscopy, and asymmetrical flow‐field flow fractionation combined with light scattering techniques. To demonstrate targeting functions of protein‐loaded polymersomes, avidin post‐functionalized polymersomes are used for the molecular recognition of biotinylated cell surface receptors. These versatile protein‐loaded polymersomes present new opportunities for designing sophisticated biomolecular nanoobjects in the field of (extracellular matrix) protein therapeutics.
    Type of Medium: Online Resource
    ISSN: 1616-5187 , 1616-5195
    URL: Issue
    URL: Article
    DOI: 10.1002/mabi.v21.10
    DOI: 10.1002/mabi.202100102
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2039130-4
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    A Poly(Propyleneimine) Dendrimer-Based Polyplex-System for Single-Chain Antibody-Mediated Targeted Delivery and Cellular Uptake of SiRNA
    Wiley ; 2017
    In:  Small Vol. 13, No. 27 ( 2017-07), p. 1700072-
    Details
    In: Small, Wiley, Vol. 13, No. 27 ( 2017-07), p. 1700072-
    Type of Medium: Online Resource
    ISSN: 1613-6810
    URL: Issue
    URL: Article
    DOI: 10.1002/smll.v13.27
    DOI: 10.1002/smll.201700072
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2168935-0
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  • 3
    Online Resource
    Online Resource
    A new approach for clinical translation of infrared spectroscopy: exploitation of the signature of glioblastoma for general brain tumor recognition
    Springer Science and Business Media LLC ; 2023
    In:  Journal of Neuro-Oncology Vol. 161, No. 1 ( 2023-01), p. 57-66
    Details
    In: Journal of Neuro-Oncology, Springer Science and Business Media LLC, Vol. 161, No. 1 ( 2023-01), p. 57-66
    Abstract: Infrared (IR) spectroscopy has the potential for tumor delineation in neurosurgery. Previous research showed that IR spectra of brain tumors are generally characterized by reduced lipid-related and increased protein-related bands. Therefore, we propose the exploitation of these common spectral changes for brain tumor recognition. Methods Attenuated total reflection IR spectroscopy was performed on fresh specimens of 790 patients within minutes after resection. Using principal component analysis and linear discriminant analysis, a classification model was developed on a subset of glioblastoma (n = 135) and non-neoplastic brain (n = 27) specimens, and then applied to classify the IR spectra of several types of brain tumors. Results The model correctly classified 82% (517/628) of specimens as “tumor” or “non-tumor”, respectively. While the sensitivity was limited for infiltrative glioma, this approach recognized GBM (86%), other types of primary brain tumors (92%) and brain metastases (92%) with high accuracy and all non-tumor samples were correctly identified. Conclusion The concept of differentiation of brain tumors from non-tumor brain based on a common spectroscopic tumor signature will accelerate clinical translation of infrared spectroscopy and related technologies. The surgeon could use a single instrument to detect a variety of brain tumor types intraoperatively in future clinical settings. Our data suggests that this would be associated with some risk of missing infiltrative regions or tumors, but not with the risk of removing non-tumor brain.
    Type of Medium: Online Resource
    ISSN: 0167-594X , 1573-7373
    URL: Article
    DOI: 10.1007/s11060-022-04204-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2007293-4
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  • 4
    Online Resource
    Online Resource
    Artificial feeder cells expressing ligands for killer cell immunoglobulin-like receptors and CD94/NKG2A for expansion of functional primary natural killer cells with tolerance to self
    Elsevier BV ; 2020
    In:  Cytotherapy Vol. 22, No. 7 ( 2020-07), p. 354-368
    Details
    In: Cytotherapy, Elsevier BV, Vol. 22, No. 7 ( 2020-07), p. 354-368
    Type of Medium: Online Resource
    ISSN: 1465-3249
    URL: Article
    DOI: 10.1016/j.jcyt.2020.02.004
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2071176-1
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  • 5
    Online Resource
    Online Resource
    DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 7 ( 2015-04-01), p. 3201-3212
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 7 ( 2015-04-01), p. 3201-3212
    Abstract: NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti–PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400330
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Online Resource
    Targeted delivery of TLR3 agonist to tumor cells with single chain antibody fragment-conjugated nanoparticles induces type I-interferon response and apoptosis
    Springer Science and Business Media LLC ; 2019
    In:  Scientific Reports Vol. 9, No. 1 ( 2019-03-01)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2019-03-01)
    Abstract: Application of Toll-like receptor (TLR) agonists is a promising approach to treat cancer. In particular, nucleic acid-based TLR agonists such as short ssRNA and dsRNA molecules, which activate endosomal TLRs, can be delivered to tumors by use of nanoparticle delivery systems. However, such delivery systems bear unspecific side effects and poor pharmacokinetics. To overcome these limitations we developed a system for targeted delivery of a 50 bp dsRNA TLR3 agonist (Riboxxol) to treat PSCA-positive tumor cells, which consists of neutravidin conjugated to mono-biotinylated dsRNA and to humanized mono-biotinylated anti-PSCA single chain antibody derivative scFv(h-AM1)-BAP. The assembly of the components resulted in the formation of nanoparticle-like immunoconjugates designated Rapid Inducer of Cellular Inflammation and Apoptosis (RICIA). Anti-PSCA-RICIA exclusively delivered Riboxxol to PSCA-positive tumor cells as well as subcutaneous tumors. Uptake of anti-PSCA-RICIA induced a type I-interferon response and apoptosis in HEK-Blue hTLR3/PSCA reporter cells and PSCA-positive HT1376 bladder cancer cells in vitro . No such effects were observed when using RICIA coupled to an unspecific control antibody or when using Riboxxol alone. Treatment of HT1376 xenografts in immune-deficient hosts with targeted delivery of TLR3 agonist did not induce adverse effects and only modestly inhibited tumor growth when compared to controls. These results suggest promising activation of innate immune response and apoptosis upon selective delivery of TLR3 agonists in tumor cells. Yet, further studies using syngeneic and orthotopic tumor models are needed to fully exploit the potential of RICIA immunoconjugates.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-019-40032-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2615211-3
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  • 7
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    Aurora B Kinase Inhibition by AZD1152 Concomitant with Tumor Treating Fields Is Effective in the Treatment of Cultures from Primary and Recurrent Glioblastomas
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 5 ( 2023-03-06), p. 5016-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 5 ( 2023-03-06), p. 5016-
    Abstract: Tumor Treating Fields (TTFields) were incorporated into the treatment of glioblastoma, the most malignant brain tumor, after showing an effect on progression-free and overall survival in a phase III clinical trial. The combination of TTFields and an antimitotic drug might further improve this approach. Here, we tested the combination of TTFields with AZD1152, an Aurora B kinase inhibitor, in primary cultures of newly diagnosed (ndGBM) and recurrent glioblastoma (rGBM). AZD1152 concentration was titrated for each cell line and 5–30 nM were used alone or in addition to TTFields (1.6 V/cm RMS; 200 kHz) applied for 72 h using the inovitro™ system. Cell morphological changes were visualized by conventional and confocal laser microscopy. The cytotoxic effects were determined by cell viability assays. Primary cultures of ndGBM and rGBM varied in p53 mutational status; ploidy; EGFR expression and MGMT-promoter methylation status. Nevertheless; in all primary cultures; a significant cytotoxic effect was found following TTFields treatment alone and in all but one, a significant effect after treatment with AZD1152 alone was also observed. Moreover, in all primary cultures the combined treatment had the most pronounced cytotoxic effect in parallel with morphological changes. The combined treatment of TTFields and AZD1152 led to a significant reduction in the number of ndGBM and rGBM cells compared to each treatment alone. Further evaluation of this approach, which has to be considered as a proof of concept, is warranted, before entering into early clinical trials.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24055016
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
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  • 8
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    Online Resource
    Prospects of immune checkpoint blockade and vaccine-based immunotherapy for glioblastoma
    Walter de Gruyter GmbH ; 2021
    In:  Innovative Surgical Sciences Vol. 6, No. 1 ( 2021-05-03), p. 35-48
    Details
    In: Innovative Surgical Sciences, Walter de Gruyter GmbH, Vol. 6, No. 1 ( 2021-05-03), p. 35-48
    Abstract: Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor endowed with a dismal prognosis. Nowadays, immunotherapy in a particular immune checkpoint blockade and therapeutic vaccines are being extensively pursued. Yet, several characteristics of GBM may impact such immunotherapeutic approaches. This includes tumor heterogeneity, the relatively low mutational load of primary GBM, insufficient delivery of antibodies to tumor parenchyma and the unique immunosuppressive microenvironment of GBM. Moreover, standard treatment of GBM, comprising temozolomide chemotherapy, radiotherapy and in most instances the application of glucocorticoids for management of brain edema, results in a further increased immunosuppression. This review will provide a brief introduction to the principles of vaccine-based immunotherapy and give an overview of the current clinical studies, which employed immune checkpoint inhibitors, oncolytic viruses-based vaccination, cell-based and peptide-based vaccines. Recent experiences as well as the latest developments are reviewed. Overcoming obstacles, which limit the induction and long-term immune response against GBM when using vaccination approaches, are necessary for the implementation of effective immunotherapy of GBM.
    Type of Medium: Online Resource
    ISSN: 2364-7485
    URL: Article
    DOI: 10.1515/iss-2020-0034
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2021
    detail.hit.zdb_id: 2876075-X
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  • 9
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    Online Resource
    CAR-mediated targeting of NK cells overcomes tumor immune escape caused by ICAM-1 downregulation
    BMJ ; 2024
    In:  Journal for ImmunoTherapy of Cancer Vol. 12, No. 2 ( 2024-02), p. e008155-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 12, No. 2 ( 2024-02), p. e008155-
    Abstract: The antitumor activity of natural killer (NK) cells can be enhanced by specific targeting with therapeutic antibodies that trigger antibody-dependent cell-mediated cytotoxicity (ADCC) or by genetic engineering to express chimeric antigen receptors (CARs). Despite antibody or CAR targeting, some tumors remain resistant towards NK cell attack. While the importance of ICAM-1/LFA-1 interaction for natural cytotoxicity of NK cells is known, its impact on ADCC induced by the ErbB2 (HER2)-specific antibody trastuzumab and ErbB2-CAR-mediated NK cell cytotoxicity against breast cancer cells has not been investigated. Methods Here we used NK-92 cells expressing high-affinity Fc receptor FcγRIIIa in combination with trastuzumab or ErbB2-CAR engineered NK-92 cells (NK-92/5.28.z) as well as primary human NK cells combined with trastuzumab or modified with the ErbB2-CAR and tested cytotoxicity against cancer cells varying in ICAM-1 expression or alternatively blocked LFA-1 on NK cells. Furthermore, we specifically stimulated Fc receptor, CAR and/or LFA-1 to study their crosstalk at the immunological synapse and their contribution to degranulation and intracellular signaling in antibody-targeted or CAR-targeted NK cells. Results Blockade of LFA-1 or absence of ICAM-1 significantly reduced cell killing and cytokine release during trastuzumab-mediated ADCC against ErbB2-positive breast cancer cells, but not so in CAR-targeted NK cells. Pretreatment with 5-aza-2'-deoxycytidine induced ICAM-1 upregulation and reversed NK cell resistance in ADCC. Trastuzumab alone did not sufficiently activate NK cells and required additional LFA-1 co-stimulation, while activation of the ErbB2-CAR in CAR-NK cells induced efficient degranulation independent of LFA-1. Total internal reflection fluorescence single molecule imaging revealed that CAR-NK cells formed an irregular immunological synapse with tumor cells that excluded ICAM-1, while trastuzumab formed typical peripheral supramolecular activation cluster (pSMAC) structures. Mechanistically, the absence of ICAM-1 did not affect cell–cell adhesion during ADCC, but rather resulted in decreased signaling via Pyk2 and ERK1/2, which was intrinsically provided by CAR-mediated targeting. Furthermore, while stimulation of the inhibitory NK cell checkpoint molecule NKG2A markedly reduced FcγRIIIa/LFA-1-mediated degranulation, retargeting by CAR was only marginally affected. Conclusions Downregulation of ICAM-1 on breast cancer cells is a critical escape mechanism from trastuzumab-triggered ADCC. In contrast, CAR-NK cells are able to overcome cancer cell resistance caused by ICAM-1 reduction, highlighting the potential of CAR-NK cells in cancer immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2023-008155
    Language: English
    Publisher: BMJ
    Publication Date: 2024
    detail.hit.zdb_id: 2719863-7
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  • 10
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    NKG2C+ NK Cells for Immunotherapy of Glioblastoma Multiforme
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 10 ( 2022-05-23), p. 5857-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 10 ( 2022-05-23), p. 5857-
    Abstract: In glioblastoma, non-classical human leucocyte antigen E (HLA-E) and HLA-G are frequently overexpressed. HLA-E loaded with peptides derived from HLA class I and from HLA-G contributes to inhibition of natural killer (NK) cells with expression of the inhibitory receptor CD94/NKG2A. We investigated whether NK cells expressing the activating CD94/NKG2C receptor counterpart were able to exert anti-glioma effects. NKG2C+ subsets were preferentially expanded by a feeder cell line engineered to express an artificial disulfide-stabilized trimeric HLA-E ligand (HLA-E*spG). NK cells expanded by a feeder cell line, which facilitates outgrowth of conventional NKG2A+, and fresh NK cells, were included for comparison. Expansion via the HLA-E*spG feeder cells selectively increased the fraction of NKG2C+ NK cells, which displayed a higher frequency of KIR2DL2/L3/S2 and CD16 when compared to expanded NKG2A+ NK cells. NKG2C+ NK cells exhibited increased cytotoxicity against K562 and KIR:HLA-matched and -mismatched primary glioblastoma multiforme (GBM) cells when compared to NKG2A+ NK cells and corresponding fresh NK cells. Cytotoxic responses of NKG2C+ NK cells were even more pronounced when utilizing target cells engineered with HLA-E*spG. These findings support the notion that NKG2C+ NK cells have potential therapeutic value for treating gliomas.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23105857
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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