Research findings related to UNITE work packages A03/B01/B03
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.
Chih YC*, Dietsch AC, Koopmann P, Ma X, Agardy DA*, Zhao B, De Roia A, Kourtesakis A, Kilian M, Krämer C, Suwala AK, Stenzinger M, Boenig H, Blum A, Pienkowski VM, Aman K, Becker JP, Feldmann H, Bunse T* , Harbottle R, Riemer AB, Liu HK* , Etminan N, Sahm F* , Ratliff M* , Wick W* , Platten M* , Green EW, Bunse L.* Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen. Nat Commun. 2025 Feb 1;16(1):1262. doi: 10.1038/s41467-025-56547-w. PMID: 39893177; PMCID: PMC11787355. * UNITE Principal Investigators and Fellows
