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  1. Artikel ; Online: Early induction of cytokine release syndrome by rapidly generated CAR T cells in preclinical models.

    Jamali, Arezoo / Ho, Naphang / Braun, Angela / Adabi, Elham / Thalheimer, Frederic B / Buchholz, Christian J

    EMBO molecular medicine

    2024  Band 16, Heft 4, Seite(n) 784–804

    Abstract: Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector ... ...

    Abstract Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector exposure, are in focus of current investigations. Their impact on the incidence and severity of CRS has been poorly explored. Here, we evaluated CD19-specific stCAR T cells in preclinical models. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and potent release of CRS-related cytokines (IL-6, IFN-γ, TNF-α, GM-CSF, IL-2, IL-10). When administered to NSG-SGM3 mice, stCAR T cells, but not conventional CAR T cells, induced severe acute adverse events within 24 h, including hypothermia and weight loss, as well as high body scores, independent of the presence of tumor target cells. Human (IFN-γ, TNF-α, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines, typical for severe CRS, were systemically elevated. Our data highlight potential safety risks of rapidly manufactured CAR T cells and suggest NSG-SGM3 mice as sensitive model for their preclinical safety evaluation.
    Mesh-Begriff(e) Humans ; Animals ; Mice ; Cytokine Release Syndrome ; Interleukin-10 ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Interleukin-2 ; Cytokines ; Immunotherapy, Adoptive ; T-Lymphocytes ; Neoplasms
    Chemische Substanzen Interleukin-10 (130068-27-8) ; Interleukin-6 ; Tumor Necrosis Factor-alpha ; Interleukin-2 ; Cytokines
    Sprache Englisch
    Erscheinungsdatum 2024-03-21
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.1038/s44321-024-00055-9
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

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  2. Buch ; Online ; Dissertation / Habilitation: Refined generation of chimeric antigen receptor T cells by dasatinib and urolithin A

    Braun, Angela [Verfasser] / Kolmar, Harald [Akademischer Betreuer] / Buchholz, Christian [Akademischer Betreuer]

    2024  

    Verfasserangabe Angela Braun ; Harald Kolmar, Christian Buchholz
    Schlagwörter Biowissenschaften, Biologie ; Life Science, Biology
    Thema/Rubrik (Code) sg570
    Sprache Englisch
    Verlag Universitäts- und Landesbibliothek
    Erscheinungsort Darmstadt
    Dokumenttyp Buch ; Online ; Dissertation / Habilitation
    Datenquelle Digitale Dissertationen im Internet

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  3. Artikel ; Online: CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.

    Charitidis, Filippos T / Adabi, Elham / Ho, Naphang / Braun, Angela H / Tierney, Ciara / Strasser, Lisa / Thalheimer, Frederic B / Childs, Liam / Bones, Jonathan / Clarke, Colin / Buchholz, Christian J

    Advanced science (Weinheim, Baden-Wurttemberg, Germany)

    2023  Band 10, Heft 35, Seite(n) e2302992

    Abstract: Lentiviral vectors (LV) have become the dominant tool for stable gene transfer into lymphocytes including chimeric antigen receptor (CAR) gene delivery to T cells, a major breakthrough in cancer therapy. Yet, room for improvement remains, especially for ... ...

    Abstract Lentiviral vectors (LV) have become the dominant tool for stable gene transfer into lymphocytes including chimeric antigen receptor (CAR) gene delivery to T cells, a major breakthrough in cancer therapy. Yet, room for improvement remains, especially for the latest LV generations delivering genes selectively into T cell subtypes, a key requirement for in vivo CAR T cell generation. Toward improving gene transfer rates with these vectors, whole transcriptome analyses on human T lymphocytes are conducted after exposure to CAR-encoding conventional vectors (VSV-LV) and vectors targeted to CD8+ (CD8-LV) or CD4+ T cells (CD4-LV). Genes related to quiescence and antiviral restriction are found to be upregulated in CAR-negative cells exposed to all types of LVs. Down-modulation of various antiviral restriction factors, including the interferon-induced transmembrane proteins (IFITMs) is achieved with rapamycin as verified by mass spectrometry (LC-MS). Strikingly, rapamycin enhances transduction by up to 7-fold for CD8-LV and CD4-LV without compromising CAR T cell activities but does not improve VSV-LV. When administered to humanized mice, CD8-LV results in higher rates of green fluorescent protein (GFP) gene delivery. Also in vivo CAR T cell generation is improved in kinetics and tumor control, however to a moderate extent, leaving room for improvement by optimizing the rapamycin administration schedule. The data favor multi-omics approaches for improvements in gene delivery.
    Mesh-Begriff(e) Humans ; Mice ; Animals ; Receptors, Chimeric Antigen/genetics ; Lentivirus/genetics ; Genetic Vectors/genetics ; Gene Transfer Techniques ; Antiviral Agents
    Chemische Substanzen Receptors, Chimeric Antigen ; Antiviral Agents
    Sprache Englisch
    Erscheinungsdatum 2023-10-30
    Erscheinungsland Germany
    Dokumenttyp Journal Article
    ZDB-ID 2808093-2
    ISSN 2198-3844 ; 2198-3844
    ISSN (online) 2198-3844
    ISSN 2198-3844
    DOI 10.1002/advs.202302992
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy.

    Denk, Dominic / Petrocelli, Valentina / Conche, Claire / Drachsler, Moritz / Ziegler, Paul K / Braun, Angela / Kress, Alena / Nicolas, Adele M / Mohs, Kathleen / Becker, Christoph / Neurath, Markus F / Farin, Henner F / Buchholz, Christian J / Andreux, Pénélope A / Rinsch, Chris / Greten, Florian R

    Immunity

    2022  Band 55, Heft 11, Seite(n) 2059–2073.e8

    Abstract: T memory stem cells ( ... ...

    Abstract T memory stem cells (T
    Mesh-Begriff(e) Mice ; Animals ; Mitophagy ; Coumarins/pharmacology ; Wnt Signaling Pathway ; Stem Cells ; Immunologic Memory
    Chemische Substanzen 3,8-dihydroxy-6H-dibenzo(b,d)pyran-6-one (1143-70-0) ; Coumarins
    Sprache Englisch
    Erscheinungsdatum 2022-10-19
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2022.09.014
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Verfügbar in ZB MED Köln/Königswinter

    Zs.A 4227: Hefte anzeigen Standort:
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  5. Artikel ; Online: Combining T-cell-specific activation and in vivo gene delivery through CD3-targeted lentiviral vectors.

    Frank, Annika M / Braun, Angela H / Scheib, Lea / Agarwal, Shiwani / Schneider, Irene C / Fusil, Floriane / Perian, Séverine / Sahin, Ugur / Thalheimer, Frederic B / Verhoeyen, Els / Buchholz, Christian J

    Blood advances

    2020  Band 4, Heft 22, Seite(n) 5702–5715

    Abstract: Genetic modification of T lymphocytes is a key issue in research and therapy. Conventional lentiviral vectors (LVs) are neither selective for T cells nor do they modify resting or minimally stimulated cells, which is crucial for applications, such as ... ...

    Abstract Genetic modification of T lymphocytes is a key issue in research and therapy. Conventional lentiviral vectors (LVs) are neither selective for T cells nor do they modify resting or minimally stimulated cells, which is crucial for applications, such as efficient in vivo modification of T lymphocytes. Here, we introduce novel CD3-targeted LVs (CD3-LVs) capable of genetically modifying human T lymphocytes without prior activation. For CD3 attachment, agonistic CD3-specific single-chain variable fragments were chosen. Activation, proliferation, and expansion mediated by CD3-LVs were less rapid compared with conventional antibody-mediated activation owing to lack of T-cell receptor costimulation. CD3-LVs delivered genes not only selectively into T cells but also under nonactivating conditions, clearly outperforming the benchmark vector vesicular stomatitis-LV glycoproteins under these conditions. Remarkably, CD3-LVs were properly active in gene delivery even when added to whole human blood in absence of any further stimuli. Upon administration of CD3-LV into NSG mice transplanted with human peripheral blood mononuclear cells, efficient and exclusive transduction of CD3+ T cells in all analyzed organs was achieved. Finally, the most promising CD3-LV successfully delivered a CD19-specific chimeric antigen receptor (CAR) into T lymphocytes in vivo in humanized NSG mice. Generation of CAR T cells was accompanied by elimination of human CD19+ cells from blood. Taken together, the data strongly support implementation of T-cell-activating properties within T-cell-targeted vector particles. These particles may be ideally suited for T-cell-specific in vivo gene delivery.
    Mesh-Begriff(e) Animals ; Genetic Vectors ; Lentivirus/genetics ; Leukocytes, Mononuclear ; Mice ; T-Lymphocytes ; Transduction, Genetic
    Sprache Englisch
    Erscheinungsdatum 2020-11-20
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2020002229
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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