Document Type
Article
Publication Date
2-2-2024
Original Citation
Krämer C,
Kilian M,
Chih Y,
Kourtesakis A,
Hoffmann D,
Boschert T,
Koopmann P,
Sanghvi K,
De Roia A,
Jung S,
Jähne K,
Day B,
Shultz LD,
Ratliff M,
Harbottle R,
Green E,
Will R,
Wick W,
Platten M,
Bunse L.
NLGN4X TCR transgenic T cells to treat gliomas. Neuro Oncol. 2024;26(2):266-78.
Keywords
JMG, Mice, Animals, Humans, Glioblastoma, Cancer Vaccines, Vaccines, Subunit, Receptors, Antigen, T-Cell, T-Lymphocytes, Antigens, Neoplasm, Cell Adhesion Molecules, Neuronal
JAX Source
Neuro Oncol. 2024;26(2):266-78.
ISSN
1523-5866
PMID
37715782
DOI
https://doi.org/10.1093/neuonc/noad172
Abstract
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.
Comments
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