TY  - JOUR
AU  - Chih, Yu-Chan
AU  - Dietsch, Amelie C
AU  - Koopmann, Philipp
AU  - Ma, Xiujian
AU  - Agardy, Dennis Alexander
AU  - Zhao, Binghao
AU  - De Roia, Alice
AU  - Kourtesakis, Alexandros
AU  - Kilian, Michael
AU  - Krämer, Christopher
AU  - Suwala, Abigail K
AU  - Stenzinger, Miriam
AU  - Boenig, Halvard
AU  - Blum, Agnieszka
AU  - Pienkowski, Victor Murcia
AU  - Aman, Kuralay
AU  - Becker, Jonas
AU  - Feldmann, Henrike
AU  - Bunse, Theresa
AU  - Harbottle, Richard
AU  - Riemer, Angelika
AU  - Liu, Haikun
AU  - Etminan, Nima
AU  - Sahm, Felix
AU  - Ratliff, Miriam
AU  - Wick, Wolfgang
AU  - Platten, Michael
AU  - Green, Edward
AU  - Bunse, Lukas
TI  - Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00269
SP  - 1262
PY  - 2025
N1  - #EA:D170#LA:D170# / DKFZ-ZMBH-Alliance / HI-TRON
AB  - 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.
KW  - Glioblastoma: therapy
KW  - Glioblastoma: immunology
KW  - Humans
KW  - Animals
KW  - Receptors, Antigen, T-Cell: immunology
KW  - Receptors, Antigen, T-Cell: metabolism
KW  - Brain Neoplasms: immunology
KW  - Brain Neoplasms: therapy
KW  - Mice
KW  - Neoplastic Stem Cells: immunology
KW  - Neoplastic Stem Cells: metabolism
KW  - Cell Line, Tumor
KW  - Cancer Vaccines: immunology
KW  - HLA-A2 Antigen: immunology
KW  - HLA-A2 Antigen: metabolism
KW  - HLA-A2 Antigen: genetics
KW  - T-Lymphocytes: immunology
KW  - T-Lymphocytes: metabolism
KW  - Immunotherapy, Adoptive: methods
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5: metabolism
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5: genetics
KW  - Antigens, Neoplasm: immunology
KW  - Antigens, Neoplasm: metabolism
KW  - Female
KW  - Receptors, Antigen, T-Cell (NLM Chemicals)
KW  - Cancer Vaccines (NLM Chemicals)
KW  - PTPRZ1 protein, human (NLM Chemicals)
KW  - HLA-A2 Antigen (NLM Chemicals)
KW  - Receptor-Like Protein Tyrosine Phosphatases, Class 5 (NLM Chemicals)
KW  - HLA-A*02 antigen (NLM Chemicals)
KW  - Antigens, Neoplasm (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39893177
C2  - pmc:PMC11787355
DO  - DOI:10.1038/s41467-025-56547-w
UR  - https://inrepo02.dkfz.de/record/298413
ER  -