CELL INTELLIGENCE · 肿瘤细胞治疗研究

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. No effective immunotherapy exists for malignant meningioma. NY-ESO-1 is widely expressed in meningiomas but not in normal cells, making it an ideal immunotherapeutic target. Engineered T cells have been used to target NY-ESO-1 in melanomas and sarcomas but not in brain tumors. We found that T cells targeting NY-ESO-1 effectively killed meningiomas in vitro, with the efficacy correlating with tumor NY-ESO-1 expression. Adoptive cell transfer of these T cells results in significantly increased survival in vivo in high-grade meningiomas. Our study demonstrated that targeting NY-ESO-1 with T cells may be a clinically feasible adjuvant immunotherapeutic strategy for treating high-grade meningiomas.