EXTH-28. NLGN4X TCR TRANSGENIC T CELLS TARGETING EXPERIMENTAL GLIOMAS. (12th November 2021)

• Record Type: Journal Article
• Authors: Krämer, Christopher; Kilian, Michael; Will, Rainer; Sanghvi, Khwab; Green, Edward; Friedrich, Mirco; Wick, Wolfgang; Platten, Michael; Bunse, Lukas
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi169
• Page End: vi169
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.667
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: The application of personalized vaccines has shown to be effective in patients with newly diagnosed glioblastoma in phase 1 clinical trials. Responses of CD8 T cells directed against the glioma-associated antigen Neuroligin-4, X-linked (NLGN4X) were reported in multipeptide vaccine trials in patients with glioblastoma. Here, we characterized the functional status of NLGN4X TCR transgenic T cells in vitro and assessed their therapeutic capacity in vivo . METHODS: TCR encoding sequences were delivered by lentiviral transduction to activated T cells from healthy donors. After confirmation of TCR surface expression T cells were used for a functional in vitro characterization. For in vivo assessment of NLGN4X-specific TCR transgenic T cells, NLGN4X-expressing U87 glioma cells were injected into the flank of NSG MHCI/MHC II knockout mice, which do not develop graft versus host disease. TCR transgenic T cells were injected intravenously on day 11 and day 18 and tumor size was monitored. RESULTS: TCR transgenic T cells depicted stable surface expression for at least 11 days in vitro after transduction. Thereby, murine TCR beta constant region positive T cells featured a polyfunctional phenotype demonstrated by a significant increase of Interferon-γ and TNF-α and remained reactive to the NLGN4X epitope for at least 7 days. Additionally, NLGN4X TCR transgenic T cells showed significantly increased antigen-specific production of the cytolytic protein granzyme B and elevated levels of perforin. In a novel xenograft mouse model NLGN4X TCR transgenic T cells slowed the tumor growth compared to the initial tumor size until day 25 after tumor inoculation. DISCUSSION: We demonstrate that NLGN4X TCR transgenic T cells specifically and consistently recognize their corresponding immunogenic sequence and target antigen-overexpressing glioma cells. We present first evidence of in vivo reactivity, while further experiments are required to assess the full therapeutic potential of NLGN4X-TCR-transgenic T cell therapy for glioma patients.