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NLGN4X TCR transgenic T cells to treat gliomas

Background.   Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumorassociated 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...

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Main Authors: Krämer, Christopher (Author) , Kilian, Michael (Author) , Chih, Yu-Chan (Author) , Kourtesakis, Alexandros (Author) , Hoffmann, Dirk C. (Author) , Boschert, Tamara (Author) , Koopmann, Philipp (Author) , Sanghvi, Khwab (Author) , De Roia, Alice (Author) , Jung, Stefanie (Author) , Jähne, Kristine (Author) , Day, Bryan (Author) , Shultz, Lenny D. (Author) , Ratliff, Miriam (Author) , Harbottle, Richard (Author) , Green, Edward W (Author) , Will, Rainer (Author) , Wick, Wolfgang (Author) , Platten, Michael (Author) , Bunse, Lukas (Author)
Format: Article (Journal)
Language:English
Published: February 2024
In: Neuro-Oncology
Year: 2024, Volume: 26, Issue: 2, Pages: 266-278
ISSN:1523-5866
DOI:10.1093/neuonc/noad172
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/neuonc/noad172
Verlag, kostenfrei, Volltext: https://academic.oup.com/neuro-oncology/advance-article/doi/10.1093/neuonc/noad172/7275527
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Author Notes:Christoper Krämer, Michael Kilian, Yu-Chan Chih, Alexandros Kourtesakis, Dirk C Hoffmann, Tamara Boschert, Philipp Koopmann, Khwab Sanghvi, Alice De Roia, Stefanie Jung, Kristine Jähne, Bryan Day, Lenny D Shultz, Miriam Ratliff, Richard Harbottle, Edward W Green, Rainer Will, Wolfgang Wick, Michael Platten, and Lukas Bunse
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Summary:Background.   Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumorassociated 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 NLGN4Xexpressing 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-specificTCR 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
Item Description:Online veröffentlicht: 16. September 2023
Gesehen am 08.01.2024
Physical Description:Online Resource
ISSN:1523-5866
DOI:10.1093/neuonc/noad172

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