Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen
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<sup>+</sup> 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.
Authors
- Alexandros Kourtesakis (ORCID: https://orcid.org/0000-0002-7894-9131)
- Theresa Bunse (ORCID: https://orcid.org/0000-0003-1834-4269)
- Abigail K. Suwala (ORCID: https://orcid.org/0009-0003-8394-1905)
- Richard P. Harbottle (ORCID: https://orcid.org/0000-0002-3332-8024)
- Lukas Bunse (ORCID: https://orcid.org/0000-0002-4490-7574)
- Agnieszka Blum (ORCID: https://orcid.org/0009-0008-3096-5440)
- Christopher M. Kramer (ORCID: https://orcid.org/0000-0003-2057-7731)
- Jonas Philipp Becker (ORCID: https://orcid.org/0000-0002-1594-9652)
- Edward W. Green (ORCID: https://orcid.org/0000-0003-1922-2298)
- Felix Sahm (ORCID: https://orcid.org/0000-0001-5441-1962)
- Michael Platten (ORCID: https://orcid.org/0000-0002-4746-887X)
- Dennis A. Agardy (ORCID: https://orcid.org/0000-0001-6900-2504)
- P. Koopmann
- Hai‐Kun Liu (ORCID: https://orcid.org/0000-0003-3338-4066)
- Miriam Stenzinger
- Halvard Boenig
- Wolfgang Wick (ORCID: https://orcid.org/0000-0002-6171-634X)
- Victor Murcia Pienkowski (ORCID: https://orcid.org/0000-0002-1383-8019)
- Alice De Roia
- Miriam Ratliff (ORCID: https://orcid.org/0000-0002-9464-6544)
- Michael Kilian (ORCID: https://orcid.org/0000-0002-1946-3174)
- Nima Etminan (ORCID: https://orcid.org/0000-0003-2832-4018)
- Angelika Beate Riemer (ORCID: https://orcid.org/0000-0002-5865-0714)
- Binghao Zhao (ORCID: https://orcid.org/0000-0002-9604-300X)
- Xiujian Ma (ORCID: https://orcid.org/0000-0002-5291-7430)
- Kuralay Aman
- Amelie Christina Dietsch
- Yu‐Chan Chih (ORCID: https://orcid.org/0000-0001-7332-0740)
- Henrike Feldmann
Institutions
- Goethe University Frankfurt (DE)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Mannheim (DE)
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- German Red Cross (DE)
- University Hospital Heidelberg (DE)
- National Center for Tumor Diseases (DE)
- Helmholtz Institute Mainz (DE)
- German Center for Infection Research (DE)
- DKFZ-ZMBH Alliance (DE)
- University Medical Centre Mannheim (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1038/s41467-025-56547-w
- Citations
- 19
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 19.86
Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Universität Heidelberg
- Deutschen Konsortium für Translationale Krebsforschung
- Swiss Bridge Foundation