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
