TY  - JOUR
AU  - Kourtesakis, Alexandros
AU  - Bailey, Eileen
AU  - Chow, Hiu Nam Hannah
AU  - Rohdjeß, Hannah
AU  - Mussnig, Normann
AU  - Agardy, Dennis Alexander
AU  - Hoffmann, Dirk Carsten Frieder
AU  - Chih, Yu-Chan
AU  - Will, Rainer
AU  - Kaulen, Leon
AU  - Hahn, Melissa
AU  - Wagener, Robin
AU  - Reibold, Denise
AU  - Pusch, Sonja
AU  - Sahm, Felix
AU  - Sauer, Tim
AU  - Schmitt, Michael
AU  - Bunse, Lukas
AU  - Platten, Michael
AU  - Wick, Wolfgang
AU  - Kessler, Tobias
TI  - Utilization of universal-targeting mSA2 CAR-T cells for the treatment of glioblastoma.
JO  - OncoImmunology
VL  - 14
IS  - 1
SN  - 2162-4011
CY  - Abingdon
PB  - Taylor & Franics
M1  - DKFZ-2025-01246
SP  - 2518631
PY  - 2025
N1  - #EA:B320#LA:B320#
AB  - 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.
KW  - Glioblastoma: therapy
KW  - Glioblastoma: immunology
KW  - Glioblastoma: pathology
KW  - Animals
KW  - Humans
KW  - Mice
KW  - Immunotherapy, Adoptive: methods
KW  - Brain Neoplasms: therapy
KW  - Brain Neoplasms: immunology
KW  - Brain Neoplasms: pathology
KW  - Receptors, Chimeric Antigen: immunology
KW  - Receptors, Chimeric Antigen: metabolism
KW  - Receptors, Chimeric Antigen: genetics
KW  - Cell Line, Tumor
KW  - Xenograft Model Antitumor Assays
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - Glioblastoma (Other)
KW  - immunotherapy (Other)
KW  - mSA2 CAR-T cells (Other)
KW  - universal antigen targeting (Other)
KW  - Receptors, Chimeric Antigen (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40518621
DO  - DOI:10.1080/2162402X.2025.2518631
UR  - https://inrepo02.dkfz.de/record/302114
ER  -