Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany; Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany.
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Immunobiology. 2023 Sep;228(5):152720. doi: 10.1016/j.imbio.2023.152720. Epub 2023 Jul 28.
Treatment of severe COVID-19 disease can be challenging in immunocompromized patients due to newly emerging virus variants of concern (VOC) escaping the humoral response. Thus, T cells recognizing to date unmutated epitopes are not only relevant for patients' immune responses against VOC, but might also serve as a therapeutic option for patients with severe COVID-19 disease in the future, e.g. following allogenic stem cell transplantation.
To this purpose, the activation, cytokine profile and specificity of T-cell clones against unmutated and omicron Spike (S)-protein was analyzed, HLA restriction was determined and most promising T-cell receptor (TCR) was introduced into allogeneic T cells via CRISPR/Cas9-mediated orthotopic TCR replacement. Finally, T-cell responses of engineered T cells was determined and durability of the TCR replacement measured.
SARS-CoV-2 specific engineered T cells recognizing a genomically stable region of the S-protein of all SARS-CoV 2 variants were successfully generated. Such transgenic T cells exhibit favorable effector functions and provide a treatment option of immunocompromised COVID-19 patients.
由于新出现的关注变异株（VOC）逃避了体液免疫反应，免疫功能低下的 COVID-19 患者的治疗可能具有挑战性。因此，识别迄今为止未突变表位的 T 细胞不仅与患者针对 VOC 的免疫反应相关，而且在未来可能成为严重 COVID-19 患者的治疗选择，例如异基因造血干细胞移植后。
为此，分析了针对未突变和奥密克戎 Spike（S）蛋白的 T 细胞克隆的激活、细胞因子谱和特异性，确定了 HLA 限制，并通过 CRISPR/Cas9 介导的同种异体 TCR 替代将最有前途的 TCR 引入同种异体 T 细胞。最后，测定了工程化 T 细胞的 T 细胞反应，并测量了 TCR 替代的耐久性。
成功地生成了针对所有 SARS-CoV-2 变体的 S 蛋白中基因组稳定区域的 SARS-CoV-2 特异性工程 T 细胞。这种转基因 T 细胞表现出有利的效应功能，并为免疫功能低下的 COVID-19 患者提供了一种治疗选择。
