Transgenic T cell therapy targeting the glioblastoma stem cell antigen PTPRZ1 with a vaccine-induced, patient-derived T cell receptor

Response to CAR-T cell therapy in glioblastoma (GB) patients is limited, particularly because of the paucity of cell surface immunotherapeutic targets or low antigen sensitivity. Moreover, tonic CAR signaling leads to T cell dysfunction eventually resulting in non-durable responses. T cell receptor-engineered T (TCR-T) cell therapy circumvents the latter limitation by allowing safe and ubiquitous targeting of the GB-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), a GB antigen associated with GB cell stemness, was previously targeted in multipeptide vaccination trials. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated GB patient. Single-cell sequencing of primary brain tumor samples showed PTPRZ1 overexpression exclusively in malignant cells and most pronounced in GB stem cells and astrocyte (AC)- or oligodendrocyte-progenitor (OPC)-like cells. The validated vaccine-induced TCR recognized the endogenously processed antigen without cross-reactivity to in silico predicted low-risk off-targets. PTPRZ1-specific TCR-engineered human primary T cells (PTPRZ1-TCR-T) killed target cells antigen-specifically. Intravenous adoptive cell transfer against experimental brain tumors alone was not efficacious, but the addition of intracerebroventricular administration of PTPRZ1-TCR-T resulted in potent tumor rejection. PTPRZ1-TCR-T maintained stem cell memory phenotype in vitro and in vivo. PTPRZ1-TCR-T lysed all examined HLA-A*02+ primary GB cell lines with a preference for slow-cycling GB stem cells (GSCs) and AC-like cells. To further develop PTPRZ1-TCR-T as off-the-shelf therapy for HLA-A*02 GB patients, a phase I first-in-human clinical trial INVENT4GB is in preparation.