NLGN4X TCR transgenic T cells to treat gliomas.

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

Neuro-oncology 2023 Sep 16

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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. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

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PMID: 37715782

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