Journal Article

DKFZ-2023-01884

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NLGN4X TCR transgenic T cells to treat gliomas.

Krämer, C. (First author)DKFZ* ; Kilian, M. (First author)DKFZ* ; Chih, Y. C.DKFZ* ; Kourtesakis, A.DKFZ* ; Hoffmann, D. C.DKFZ* ; Boschert, T.DKFZ* ; Koopmann, P.DKFZ* ; Sanghvi, K.DKFZ* ; De Roia, A.DKFZ* ; Jung, S.DKFZ* ; Jähne, K.DKFZ* ; Day, B. ; Shultz, L. D. ; Ratliff, M. ; Harbottle, R.DKFZ* ; Green, E. W.DKFZ* ; Will, R.DKFZ* ; Wick, W.DKFZ* ; Platten, M.DKFZ* ; Bunse, L. (Last author)DKFZ*

2024
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/neuonc/noad172

Abstract: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A2-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.T cell receptor (TCR) discovery was performed using droplet-based single cell TCR sequencing of NLGN4X-tetramer-sorted T cells post vaccination. 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.An HLA-A *02-restricted vaccine-induced T cell receptor specifically binding NLGN4X131-139 was applied for therapeutic use. Reactivity, cytotoxicity, and polyfunctionality of this NLGN4X-specific TCR is demonstrated in various cellular models. Intracerebroventricular administration of NLGN4X-TCR-T prolongs survival and leads to an objective response rate (ORR) of 44.4 % in experimental gliomas-bearing NSG MHC I/II KO mice compared to 0.0 % in control groups, respectively.NLGN4X-TCR-T demonstrates efficacy in a preclinical glioblastoma model. On a global scale, we provide first evidence for the therapeutic retrieval of vaccine-induced human TCRs for the off-the-shelf treatment of glioblastoma patients.

Note: HI-TRON / #EA:D170#LA:D170# / 2024 Feb 2;26(2):266-278

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Contributing Institute(s):

1. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
2. DKTK HD zentral (HD01)
3. KKE Neuroonkologie (B320)
4. DNA-Vektoren (F160)
5. Zelluläre Tools (W111)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2023

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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