用TCR转导的T细胞对恶性脑膜瘤中的NY-ESO-1进行免疫治疗靶向

Immunotherapeutic targeting of NY-ESO-1 in malignant meningiomas with TCR-transduced T-cells.

作者信息

Sun Matthew Z, Contreras Erick, Treger Janet, Imbroane Marisa, Orpilla Joey, Ko Myungjun, Reynoso Jeremy, Khattab Sara, Lai Thomas J, Tsang Jonathan E, Vitte Jeremie, Giovannini Marco, Liau Linda M, Prins Robert, Everson Richard G

机构信息

University of Texas Southwestern School of Medicine, 5323 Harry Hines Blvd Mail Ext Code: 8855, Dallas, TX, 75390, USA.

University of California Los Angeles, 300 Stein Plaza Driveway Suite 420, Los Angeles, CA, 90095, USA.

出版信息

J Neurooncol. 2025 Aug 13. doi: 10.1007/s11060-025-05200-z.

DOI:10.1007/s11060-025-05200-z

PMID:40802116

Abstract

INTRODUCTION

Malignant meningiomas lack effective immunotherapeutic options. NY-ESO-1 is a potential immunotherapeutic target, because it is the most frequently expressed cancer-testis-antigen in meningiomas. We investigated the efficacy of T-Cell-Receptor-Transduced T-Cells (TCR-T) targeting NY-ESO-1 in vitro and in vivo in meningiomas.

METHODS

Immunohistochemistry was performed on Grade I-III meningioma specimens. Primary meningioma culture LB3750(Grade I) and immortalized cultures SF1335(Grade I) and CH157-HLA-A2.1(Grade III) were established and maintained in vitro. NY-ESO-1 TCR-T (HLA-A2.1 restricted) cells were co-cultured with primary and immortalized meningioma cells and assessed for real-time tumor killing in vitro. Immunodeficient NSG mice were intracranially implanted with CH157-HLA-A2.1 and SF1335 cells, treated with systemic adoptive cell transfer (ACT) of TCR-T, and assessed for overall survival in vivo.

RESULTS

NY-ESO-1 expression correlated with tumor grade (n = 35; p < 0.01). High NY-ESO-1 nuclear expression predicted a worse progression-free-survival (p = 0.0167). CH157-HLA-A2.1 cells, with native high NY-ESO-1 expression, experienced > 60% and then nearly 100% cytolysis after co-culture with TCR-T for 10 and 24 h, respectively, compared with control T-cells (p < 0.0001). SF1335 and LB3750 cells, with low NY-ESO-1 expression, experienced 20% cytolysis after 24 h of co-culture with TCR-T compared to the control (p < 0.0001). Systemic ACT of TCR-T significantly increased the median overall survival in NSG mice bearing intracranial xenografts of CH157-HLA-A2.1 by 49% (p < 0.001).

CONCLUSIONS

NY-ESO-1 TCR-T induces cytolysis in meningiomas in vitro, and its efficacy correlates with NY-ESO-1 expression. Systemic ACT results in significantly increased survival in vivo in high-grade meningioma. Therefore, targeting NY-ESO-1 may be a clinically feasible immunotherapeutic strategy for treating high-grade meningiomas.

摘要

引言

恶性脑膜瘤缺乏有效的免疫治疗方案。NY-ESO-1是一个潜在的免疫治疗靶点，因为它是脑膜瘤中最常表达的癌胚抗原。我们研究了靶向NY-ESO-1的T细胞受体转导T细胞（TCR-T）在脑膜瘤体内外的疗效。

方法

对I-III级脑膜瘤标本进行免疫组织化学检测。建立并体外培养原代脑膜瘤培养物LB3750（I级）、永生化培养物SF1335（I级）和CH157-HLA-A2.1（III级）。将NY-ESO-1 TCR-T（HLA-A2.1限制型）细胞与原代和永生化脑膜瘤细胞共培养，并评估其体外实时肿瘤杀伤能力。将免疫缺陷的NSG小鼠颅内植入CH157-HLA-A2.1和SF1335细胞，用TCR-T进行全身过继性细胞转移（ACT）治疗，并评估其体内总生存期。

结果

NY-ESO-1表达与肿瘤分级相关（n = 35；p < 0.01）。NY-ESO-1高核表达预示着无进展生存期更差（p = 0.0167）。与对照T细胞相比，天然高表达NY-ESO-1的CH157-HLA-A2.1细胞与TCR-T共培养10小时和24小时后，分别经历了>60%和近100%的细胞溶解（p < 0.0001）。NY-ESO-1低表达的SF1335和LB3750细胞与TCR-T共培养24小时后，与对照相比经历了20%的细胞溶解（p < 0.0001）。TCR-T的全身ACT显著提高了颅内接种CH157-HLA-A2.1的NSG小鼠的中位总生存期49%（p < 0.001）。