Journal Article

DKFZ-2025-01246

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Utilization of universal-targeting mSA2 CAR-T cells for the treatment of glioblastoma.

Kourtesakis, A. (First author)DKFZ* ; Bailey, E.DKFZ* ; Chow, H. N. H.DKFZ* ; Rohdjeß, H.DKFZ* ; Mussnig, N.DKFZ* ; Agardy, D. A.DKFZ* ; Hoffmann, D. C. F.DKFZ* ; Chih, Y.-C.DKFZ* ; Will, R.DKFZ* ; Kaulen, L.DKFZ* ; Hahn, M.DKFZ* ; Wagener, R.DKFZ* ; Reibold, D.DKFZ* ; Pusch, S.DKFZ* ; Sahm, F.DKFZ* ; Sauer, T. ; Schmitt, M. ; Bunse, L.DKFZ* ; Platten, M.DKFZ* ; Wick, W.DKFZ* ; Kessler, T. (Last author)DKFZ*

2025
Taylor & Franics Abingdon

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Please use a persistent id in citations: doi:10.1080/2162402X.2025.2518631

Abstract: 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.

Keyword(s): Glioblastoma: therapy (MeSH) ; Glioblastoma: immunology (MeSH) ; Glioblastoma: pathology (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Brain Neoplasms: therapy (MeSH) ; Brain Neoplasms: immunology (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Receptors, Chimeric Antigen: metabolism (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; Glioblastoma ; immunotherapy ; mSA2 CAR-T cells ; universal antigen targeting ; Receptors, Chimeric Antigen

Note: #EA:B320#LA:B320#

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Contributing Institute(s):

1. KKE Neuroonkologie (B320)
2. DKTK HD zentral (HD01)
3. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
4. Zelluläre Tools (W111)
5. KKE Neuropathologie (B300)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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