PTPRZ1 was upregulated in GBM samples and was associated with cell stemness (GSC score). Analysis of PTPRZ1-reactive T cells from a vaccinated patient yielded a TCR that was strongly activated by primary GBM cells, with no observed cross-reactivity. PTPRZ1 TCR T cells were stem cell memory-like, persistent in vivo, and effective upon iv/icv treatment in the U87 orthotopic model. However, antigen expression was lost in treated tumors, which likely underscored high rates of relapse. In primary organoid models, TCR T cells primarily targeted “slow-cycling”/stem-like tumor cells, and PTPRZ expression in residual cells was greatly reduced.
Contributed by Morgan Janes
ABSTRACT: 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.
Author Info: (1) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, co
Author Info: (1) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. (2) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. (3) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. (4) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Division of Molecular Neurogenetics, DKFZ, DKFZ-ZMBH alliance, Heidelberg, Germany. (5) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. (6) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. (7) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. DNA Vector Laboratory, DKFZ, Heidelberg, Germany. (8) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany. CCU Neurooncology, DKFZ, Heidelberg, Germany. (9) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (10) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. (11) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Institute for Pathology, Department of Neuropathology, Heidelberg University, Heidelberg, Germany. CCU Neuropathology, DKFZ, Heidelberg, Germany. (12) Institute for Clinical Transfusion Medicine and Cell Therapy, Heidelberg, Germany. Institute for Immunology, Heidelberg University Hospital, Heidelberg, Germany. (13) Faculty of Medicine, Goethe University, Frankfurt a.M., Frankfurt, Germany. Institute for Transfusion Medicine and Immunohematology, German Red Cross Blood Service Baden-Wrttemberg-Hessen, Frankfurt a.M., Frankfurt, Germany. (14) Ardigen, ul. Podole 76, Krakw, Poland. (15) Ardigen, ul. Podole 76, Krakw, Poland. (16) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. (17) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Division of Immunotherapy and Immunoprevention, DKFZ, Heidelberg, Germany. Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. (18) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. (19) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. (20) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. DNA Vector Laboratory, DKFZ, Heidelberg, Germany. (21) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Division of Immunotherapy and Immunoprevention, DKFZ, Heidelberg, Germany. Molecular Vaccine Design, German Center for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. (22) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Division of Molecular Neurogenetics, DKFZ, DKFZ-ZMBH alliance, Heidelberg, Germany. (23) Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany. (24) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Institute for Pathology, Department of Neuropathology, Heidelberg University, Heidelberg, Germany. CCU Neuropathology, DKFZ, Heidelberg, Germany. (25) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. CCU Neurooncology, DKFZ, Heidelberg, Germany. Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany. (26) German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Neurology Clinic, Heidelberg University Hospital, Heidelberg, Germany. CCU Neurooncology, DKFZ, Heidelberg, Germany. (27) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. Immune Monitoring Unit, National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany. Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz) - A Helmholtz Institute of the DKFZ, Mainz, Germany. DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany. (28) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. (29) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. l.bunse@dkfz.de. German Cancer Consortium (DKTK), DKFZ, core center Heidelberg, Heidelberg, Germany. l.bunse@dkfz.de. Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany. l.bunse@dkfz.de. DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany. l.bunse@dkfz.de.
