PMID- 37715782
OWN - NLM
STAT- MEDLINE
DCOM- 20240205
LR  - 20240229
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 26
IP  - 2
DP  - 2024 Feb 2
TI  - NLGN4X TCR transgenic T cells to treat gliomas.
PG  - 266-278
LID - 10.1093/neuonc/noad172 [doi]
AB  - BACKGROUND: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen 
      (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, 
      that was found to induce specific cytotoxic T cell responses following 
      multi-peptide vaccination in patients with newly diagnosed glioblastoma. METHODS: 
      T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR 
      sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR 
      was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T). 
      Functional profiling of NLGN4X-TCR-T was performed by flow cytometry and 
      cytotoxicity assays. Therapeutic efficacy of intracerebroventricular NLGN4X-TCR-T 
      was assessed in NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II 
      knockout (KO) (NSG MHC I/II KO) mice bearing NLGN4X-expressing experimental 
      gliomas. RESULTS: An HLA-A*02-restricted vaccine-induced T cell receptor 
      specifically binding NLGN4X131-139 was applied for preclinical therapeutic use. 
      Reactivity, cytotoxicity, and polyfunctionality of this NLGN4X-specific TCR are 
      demonstrated in various cellular models. Intracerebroventricular administration 
      of NLGN4X-TCR-T prolongs survival and leads to an objective response rate of 
      44.4% in experimental glioma-bearing NSG MHC I/II KO mice compared to 0.0% in 
      control groups. CONCLUSION: NLGN4X-TCR-T demonstrate efficacy in a preclinical 
      glioblastoma model. On a global scale, we provide the first evidence for the 
      therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf 
      treatment of glioblastoma patients.Keywords cell therapy | glioblastoma | T cell 
      receptor | tumor antigen.
CI  - (c) The Author(s) 2023. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology.
FAU - Kramer, Christoper
AU  - Kramer C
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
FAU - Kilian, Michael
AU  - Kilian M
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
FAU - Chih, Yu-Chan
AU  - Chih YC
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
FAU - Kourtesakis, Alexandros
AU  - Kourtesakis A
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
AD  - Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, 
      Heidelberg, Germany.
AD  - DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
FAU - Hoffmann, Dirk C
AU  - Hoffmann DC
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
AD  - Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, 
      Heidelberg, Germany.
AD  - DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
FAU - Boschert, Tamara
AU  - Boschert T
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
AD  - Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany.
FAU - Koopmann, Philipp
AU  - Koopmann P
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
FAU - Sanghvi, Khwab
AU  - Sanghvi K
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
FAU - De Roia, Alice
AU  - De Roia A
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
AD  - Faculty of Bioscience, Heidelberg University, Heidelberg, Germany.
AD  - DNA Vector Laboratory, DKFZ, Heidelberg, Germany.
FAU - Jung, Stefanie
AU  - Jung S
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Jahne, Kristine
AU  - Jahne K
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Day, Bryan
AU  - Day B
AD  - Faculty of Medicine, University of Queensland, Herston, Australia.
AD  - Cell and Molecular Biology Department, Sid Faithfull Brain Cancer Laboratory, 
      QIMR Berghofer MRI, Brisbane, Australia.
AD  - School of Biomedical Sciences, Faculty of Health, Queensland University of 
      Technology, Gardens Point, Australia.
FAU - Shultz, Lenny D
AU  - Shultz LD
AD  - Department of Immunology, The Jackson Laboratory, Bar Harbor, Maine, USA.
FAU - Ratliff, Miriam
AU  - Ratliff M
AD  - Department of Neurosurgery, University Hospital Mannheim, Mannheim, Germany.
FAU - Harbottle, Richard
AU  - Harbottle R
AD  - DNA Vector Laboratory, DKFZ, Heidelberg, Germany.
FAU - Green, Edward W
AU  - Green EW
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
FAU - Will, Rainer
AU  - Will R
AD  - Neurology Clinic, Heidelberg University Hospital, University of Heidelberg, 
      Heidelberg, Germany.
AD  - DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
AD  - Core Facility Cellular tools, DKFZ, Heidelberg, Germany.
FAU - Wick, Wolfgang
AU  - Wick W
FAU - Platten, Michael
AU  - Platten M
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
AD  - Helmholtz Institute of Translational Oncology (HI-TRON), Mainz, Germany.
AD  - Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, 
      Germany.
AD  - DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, 
      Germany.
FAU - Bunse, Lukas
AU  - Bunse L
AD  - German Cancer Consortium (DKTK) Clinical Cooperation Unit (CCU) Neuroimmunology 
      and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, 
      Germany.
AD  - Department of Neurology, MCTN, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
AD  - DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, 
      Germany.
LA  - eng
GR  - P30 CA034196/CA/NCI NIH HHS/United States
GR  - R01 AG032963/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Cancer Vaccines)
RN  - 0 (Vaccines, Subunit)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (NLGN4X protein, human)
RN  - 0 (Cell Adhesion Molecules, Neuronal)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - *Glioblastoma/genetics/therapy
MH  - *Cancer Vaccines/therapeutic use
MH  - Vaccines, Subunit
MH  - Receptors, Antigen, T-Cell
MH  - T-Lymphocytes
MH  - Antigens, Neoplasm/genetics
MH  - Cell Adhesion Molecules, Neuronal
PMC - PMC10836769
OTO - NOTNLM
OT  - Keywords cell therapy
OT  - T cell receptor
OT  - glioblastoma
OT  - tumor antigen
COIS- T-cell receptor-derived binding polypeptides PCT/EP2023/061716 to L.B., E.G., 
      M.P, Y.C.C, W.W., M.K., and C.K. Non-integrating DNA vectors for the genetic 
      modification of cells WO2019060253A1 to R.H. Honoraria from Adaptive 
      Biotechnologies to L.B. Consulting fees from Servier, Bayer, GSK, MSD, and Roche 
      to W.W. Royalties are received from The Jackson Laboratory from their licensing 
      NSG MHC class I/II knockout mice to For Profit Companies by L.D.S.
EDAT- 2023/09/16 20:42
MHDA- 2024/02/05 06:42
PMCR- 2023/09/16
CRDT- 2023/09/16 10:52
PHST- 2024/02/05 06:42 [medline]
PHST- 2023/09/16 20:42 [pubmed]
PHST- 2023/09/16 10:52 [entrez]
PHST- 2023/09/16 00:00 [pmc-release]
AID - 7275527 [pii]
AID - noad172 [pii]
AID - 10.1093/neuonc/noad172 [doi]
PST - ppublish
SO  - Neuro Oncol. 2024 Feb 2;26(2):266-278. doi: 10.1093/neuonc/noad172.