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Utilization of universal-targeting mSA2 CAR-T cells for the treatment of glioblastoma

Glioblastoma (GB) remains refractory to chimeric antigen receptor (CAR)-T cell therapy, mainly attributed to tumor heterogeneity and antigen escape. CAR-T cells utilizing monomeric streptavidin-2 (mSA2) instead of a traditional target binding domain, bind biotinylated antibodies and can be directed...

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Main Authors: Kourtesakis, Alexandros (Author) , Bailey, Eileen (Author) , Chow, Hiu Nam Hannah (Author) , Rohdjeß, Hannah (Author) , Mussnig, Normann (Author) , Agardy, Dennis (Author) , Hoffmann, Dirk C. (Author) , Chih, Yu-Chan (Author) , Will, Rainer D. (Author) , Kaulen, Leon D. (Author) , Hahn, Melissa (Author) , Wagener, Jan Robin (Author) , Reibold, Denise (Author) , Pusch, Sonja (Author) , Sahm, Felix (Author) , Sauer, Tim (Author) , Schmitt, Michael (Author) , Bunse, Lukas (Author) , Platten, Michael (Author) , Wick, Wolfgang (Author) , Keßler, Tobias (Author)
Format: Article (Journal)
Language:English
Published: 15 Jun 2025
In: OncoImmunology
Year: 2025, Volume: 14, Issue: 1, Pages: 1-19
ISSN:2162-402X
DOI:10.1080/2162402X.2025.2518631
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1080/2162402X.2025.2518631
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Author Notes:Alexandros Kourtesakis, Eileen Bailey, Hiu Nam Hannah Chow, Hannah Rohdjeß, Normann Mussnig, Dennis Alexander Agardy, Dirk Carsten Frieder Hoffmann, Yu-Chan Chih, Rainer Will, Leon Kaulen, Melissa Hahn, Robin Wagener, Denise Reibold, Sonja Pusch, Felix Sahm, Tim Sauer, Michael Schmitt, Lukas Bunse, Michael Platten, Wolfgang Wick, and Tobias Kessler
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Summary:Glioblastoma (GB) remains refractory to chimeric antigen receptor (CAR)-T cell therapy, mainly attributed to tumor heterogeneity and antigen escape. CAR-T cells utilizing monomeric streptavidin-2 (mSA2) instead of a traditional target binding domain, bind biotinylated antibodies and can be directed to variable targets to mediate anti-tumor effects. Although such an approach might circumvent the aforementioned challenges, the potential of mSA2 CAR-T cells for brain tumor treatment remains unexplored. In this study, we generated mSA2 CAR-T cells and tested their efficacy against GB by tailoring their specificity toward GB-associated markers CD276, EPHA2, CD70 and IL13Ra2. In vitro, mSA2 CAR-T cells specifically recognized multiple primary GB cell lines in a target- and biotinylated antibody-dependent manner. Moreover, in heterogenous tumor environments, mSA2 CAR-T cells simultaneously targeted multiple subpopulations, guided by combinations of biotinylated antibodies, indicating their potential to address tumor heterogeneity. Finally, the mSA2 CAR-T cell-mediated anti-tumor functions were demonstrated in vivo. Immunocompromised mice orthotopically implanted with CD70+ or CD276+ GB cells and treated with mSA2 CAR-T cells pre-armed with antibodies against these two antigens exhibited control of tumor growth and induction of GB cell apoptosis after therapy. Taken together, our study suggests that antibody-guided mSA2 CAR-T cells can target potentially any surface GB-related antigen both in vitro and in vivo, either univalently or multivalently, with underlined clinical implications.
Item Description:Gesehen am 21.08.2025
Physical Description:Online Resource
ISSN:2162-402X
DOI:10.1080/2162402X.2025.2518631

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