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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
February 2024
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| In: |
Neuro-Oncology
Year: 2024, Jahrgang: 26, Heft: 2, Pages: 266-278 |
| ISSN: | 1523-5866 |
| DOI: | 10.1093/neuonc/noad172 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a NLGN4X TCR transgenic T cells to treat gliomas |c 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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| 520 | |a 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 | ||
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