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 + 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. Vaccination in glioblastomas does lead to the emergence of tumour-antigen-specific T cells but T cell dysfunction, poor tumour infiltration and persistence hinder efficient tumour killing. Here authors identify a T cell receptor in a vaccinated glioblastoma patient that specifically recognizes the glioblastoma stem cell antigen PTPRZ1 and utilise it in T cell receptor-engineered T (TCR-T) cell therapy, resulting in efficient tumour cell killing in vitro and in a mouse model.