| First Author | Kr?mer C | Year | 2024 |
| Journal | Neuro Oncol | Volume | 26 |
| Issue | 2 | Pages | 266-278 |
| PubMed ID | 37715782 | Mgi Jnum | J:341654 |
| Mgi Id | MGI:7541169 | Doi | 10.1093/neuonc/noad172 |
| Citation | Kramer C, et al. (2023) NLGN4X TCR transgenic T cells to treat gliomas. Neuro Oncol |
| abstractText | BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. |
