肿瘤细胞治疗研究
英文原题：Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors.
Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors.
T 细胞受体（TCR）融合构建体（TRuC）T 细胞利用 TCR 的全部信号亚基激活 T 细胞并清除肿瘤细胞，且细胞因子释放极少。
T 细胞受体融合构建体（TRuC）T 细胞可利用 TCR 的全部信号亚基来活化 T 细胞并清除肿瘤细胞，同时仅少量释放细胞因子。嵌合抗原受体（CAR）T 细胞过继治疗对 B 细胞恶性肿瘤取得了前所未有的临床疗效，但 CAR-T 单药治疗实体瘤的临床疗效仍不理想，可能是因为 CAR 的信号特征并非天然生理模式。TRuC-T 细胞或可解决现有 CAR-T 疗法治疗实体瘤疗效不足的问题。本文报告，靶向间皮素（MSLN）的 TRuC-T 细胞（称 TC-210 T 细胞）在体外可强效杀伤 MSLN⁺ 肿瘤细胞，并在异种移植小鼠肿瘤模型中有效清除 MSLN⁺ 间皮瘤、肺癌和卵巢癌。与靶向 MSLN 的 BB CAR-T 细胞（MSLN-BB CAR-T）比较，TC-210 T 细胞总体疗效相当；但 TC-210 T 细胞始终表现出更快的肿瘤清除动力学，并伴有更早的肿瘤内积累和活化迹象。此外，体外和离体代谢分析提示，与 MSLN-BB CAR-T 相比，TC-210 T 细胞糖酵解活性较低、线粒体代谢较高。这些数据表明 TC-210 T 细胞是治疗 MSLN 表达型癌症的有前景细胞疗法。其与 CAR-T 不同的特征可能使 TRuC-T 细胞治疗实体瘤时具有更好的疗效和安全性。
T cell Receptor (TCR) Fusion Construct (TRuC ) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BB CAR-T cells (MSLN-BB CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BB CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.
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