Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen

Yu-Chan Chih, Amelie C. Dietsch, Philipp Koopmann, Xiujian Ma, Dennis A. Agardy, Binghao Zhao, Alice De Roia, Alexandros Kourtesakis, Michael Kilian, Christopher Krämer, Abigail K. Suwala, Miriam Stenzinger, Halvard Boenig, Agnieszka Blum, Victor Murcia Pienkowski, Kuralay Aman, Jonas P. Becker, Henrike Feldmann, Theresa Bunse, Richard Harbottle, Angelika B. Riemer, Hai-Kun Liu, Nima Etminan, Felix Sahm, Miriam Ratliff, Wolfgang Wick, Michael Platten, Edward W. Green and Lukas Bunse ()
Additional contact information
Yu-Chan Chih: German Cancer Research Center (DKFZ)
Amelie C. Dietsch: German Cancer Research Center (DKFZ)
Philipp Koopmann: German Cancer Research Center (DKFZ)
Xiujian Ma: core center Heidelberg
Dennis A. Agardy: German Cancer Research Center (DKFZ)
Binghao Zhao: German Cancer Research Center (DKFZ)
Alice De Roia: German Cancer Research Center (DKFZ)
Alexandros Kourtesakis: core center Heidelberg
Michael Kilian: German Cancer Research Center (DKFZ)
Christopher Krämer: German Cancer Research Center (DKFZ)
Abigail K. Suwala: core center Heidelberg
Miriam Stenzinger: Institute for Clinical Transfusion Medicine and Cell Therapy
Halvard Boenig: Frankfurt a.M.
Agnieszka Blum: ul. Podole 76
Victor Murcia Pienkowski: ul. Podole 76
Kuralay Aman: German Cancer Research Center (DKFZ)
Jonas P. Becker: core center Heidelberg
Henrike Feldmann: German Cancer Research Center (DKFZ)
Theresa Bunse: German Cancer Research Center (DKFZ)
Richard Harbottle: core center Heidelberg
Angelika B. Riemer: core center Heidelberg
Hai-Kun Liu: core center Heidelberg
Nima Etminan: University Hospital Mannheim
Felix Sahm: core center Heidelberg
Miriam Ratliff: core center Heidelberg
Wolfgang Wick: core center Heidelberg
Michael Platten: German Cancer Research Center (DKFZ)
Edward W. Green: German Cancer Research Center (DKFZ)
Lukas Bunse: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56547-w

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