Bispecific antibodies (biAbs) used in cancer immunotherapies rely on functional autologous T cells, which are often damaged and depleted in patients with haematological malignancies and in other immunocompromised patients. The adoptive transfer of allogeneic T cells from healthy donors can enhance the efficacy of biAbs, but donor T cells binding to host-cell antigens cause an unwanted alloreactive response. Here we show that allogeneic T cells engineered with a T-cell receptor that does not convert antigen binding into cluster of differentiation 3 (CD3) signalling decouples antigen-mediated T-cell activation from T-cell cytotoxicity while preserving the surface expression of the T-cell-receptor–CD3 signalling complex as well as biAb-mediated CD3 signalling and T-cell activation. In mice with CD19⁺ tumour xenografts, treatment with the engineered human cells in combination with blinatumomab (a clinically approved biAb) led to the recognition and clearance of tumour cells in the absence of detectable alloreactivity. Our findings support the development of immunotherapies combining biAbs and ‘off-the-shelf’ allogeneic T cells.

癌症免疫疗法中使用的双特异性抗体 （biAbs） 依赖于功能性自体 T 细胞，这些细胞在血液系统恶性肿瘤患者和其他免疫功能低下患者中通常会受损和耗尽。来自健康供体的同种异体 T 细胞的过继转移可以增强 biAb 的功效，但供体 T 细胞与宿主细胞抗原结合会引起不需要的同种异体反应反应。在这里，我们表明，用不将抗原结合转化为分化簇 3 （CD3） 信号传导的 T 细胞受体改造的同种异体 T 细胞将抗原介导的 T 细胞活化与 T 细胞毒性解耦，同时保留 T 细胞受体-CD3 信号复合物的表面表达以及 BiAb 介导的 CD3 信号传导和 T 细胞活化。在具有 CD19 ⁺ 肿瘤异种移植物的小鼠中，用工程化的人类细胞与 blinatumomab （一种临床批准的 biAb） 联合治疗导致在没有可检测的同种异体反应的情况下识别和清除肿瘤细胞。我们的研究结果支持结合 biAb 和“现成”同种异体 T 细胞的免疫疗法的开发。