Journal Article

DKFZ-2025-00269

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.

Chih, Y.-C. (First author)DKFZ* ; Dietsch, A. C.DKFZ* ; Koopmann, P.DKFZ* ; Ma, X.DKFZ* ; Agardy, D. A.DKFZ* ; Zhao, B.DKFZ* ; De Roia, A.DKFZ* ; Kourtesakis, A.DKFZ* ; Kilian, M.DKFZ* ; Krämer, C.DKFZ* ; Suwala, A. K.DKFZ* ; Stenzinger, M. ; Boenig, H. ; Blum, A. ; Pienkowski, V. M. ; Aman, K.DKFZ* ; Becker, J.DKFZ* ; Feldmann, H.DKFZ* ; Bunse, T.DKFZ* ; Harbottle, R.DKFZ* ; Riemer, A.DKFZ* ; Liu, H.DKFZ* ; Etminan, N. ; Sahm, F.DKFZ* ; Ratliff, M.DKFZ* ; Wick, W.DKFZ* ; Platten, M.DKFZ* ; Green, E.DKFZ* ; Bunse, L. (Last author)DKFZ*

2025
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-025-56547-w

Abstract: T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02+ primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma.

Keyword(s): Glioblastoma: therapy (MeSH) ; Glioblastoma: immunology (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Receptors, Antigen, T-Cell: immunology (MeSH) ; Receptors, Antigen, T-Cell: metabolism (MeSH) ; Brain Neoplasms: immunology (MeSH) ; Brain Neoplasms: therapy (MeSH) ; Mice (MeSH) ; Neoplastic Stem Cells: immunology (MeSH) ; Neoplastic Stem Cells: metabolism (MeSH) ; Cell Line, Tumor (MeSH) ; Cancer Vaccines: immunology (MeSH) ; HLA-A2 Antigen: immunology (MeSH) ; HLA-A2 Antigen: metabolism (MeSH) ; HLA-A2 Antigen: genetics (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5: metabolism (MeSH) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5: genetics (MeSH) ; Antigens, Neoplasm: immunology (MeSH) ; Antigens, Neoplasm: metabolism (MeSH) ; Female (MeSH) ; Receptors, Antigen, T-Cell ; Cancer Vaccines ; PTPRZ1 protein, human ; HLA-A2 Antigen ; Receptor-Like Protein Tyrosine Phosphatases, Class 5 ; HLA-A*02 antigen ; Antigens, Neoplasm

Note: #EA:D170#LA:D170# / DKFZ-ZMBH-Alliance / HI-TRON

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Contributing Institute(s):

1. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
2. DKTK HD zentral (HD01)
3. A240 Molekulare Neurogenetik (A240)
4. DNA-Vektoren (D420)
5. KKE Neuroonkologie (B320)
6. KKE Neuropathologie (B300)
7. Immuntherapie und -prävention (D410)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2025

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