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 (biAb) 依赖于功能性自体 T 细胞，而这些 T 细胞在血液恶性肿瘤患者和其他免疫功能低下的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。在这里，我们展示了用 T 细胞受体改造的同种异体 T 细胞，该受体不会将抗原结合转化为分化簇 3 (CD3) 信号传导，从而将抗原介导的 T 细胞激活与 T 细胞细胞毒性解耦，同时保留 T 细胞的表面表达。 -细胞-受体-CD3信号传导复合物以及biAb介导的CD3信号传导和T细胞激活。在具有 CD19 ⁺肿瘤异种移植物的小鼠中，使用工程化人类细胞与 blinatumomab（一种临床批准的 biAb）联合治疗，在没有可检测到的同种异体反应性的情况下导致肿瘤细胞的识别和清除。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。