Several cancer immunotherapy approaches, such as immune checkpoint blockade and adoptive T-cell therapy, boost T-cell activity against the tumor, but these strategies are not effective in the absence of T cells specific for displayed tumor antigens. Here we outline an immunotherapy in which endogenous T cells specific for a noncancer antigen are retargeted to attack tumors. The approach relies on the use of antibody–peptide epitope conjugates (APECs) to deliver suitable antigens to the tumor surface for presention by HLA-I. To retarget cytomegalovirus (CMV)-specific CD8⁺ T cells against tumors, we used APECs containing CMV-derived epitopes conjugated to tumor-targeting antibodies via metalloprotease-sensitive linkers. These APECs redirect pre-existing CMV immunity against tumor cells in vitro and in mouse cancer models. In vitro, APECs activated specifically CMV-reactive effector T cells whereas a bispecific T-cell engager activated both effector and regulatory T cells. Our approach may provide an effective alternative in cancers that are not amenable to checkpoint inhibitors or other immunotherapies.

几种癌症免疫治疗方法，例如免疫检查点阻断和过继性 T 细胞疗法，可以增强 T 细胞针对肿瘤的活性，但在缺乏针对所展示的肿瘤抗原的 T 细胞特异性的情况下，这些策略无效。在这里，我们概述了一种免疫疗法，其中对非癌抗原具有特异性的内源性 T 细胞被重新定位以攻击肿瘤。该方法依赖于使用抗体-肽表位缀合物 (APEC) 将合适的抗原递送至肿瘤表面，供 HLA-I 呈递。为了将巨细胞病毒 (CMV) 特异性 CD8 ⁺ T 细胞重新靶向肿瘤，我们使用含有通过金属蛋白酶敏感接头与肿瘤靶向抗体缀合的 CMV 衍生表位的 APEC。这些 APEC 在体外和小鼠癌症模型中重定向了针对肿瘤细胞的先前存在的 CMV 免疫。在体外，APEC 特异性激活 CMV 反应性效应 T 细胞，而双特异性 T 细胞接合剂则激活效应 T 细胞和调节性 T 细胞。我们的方法可能为那些不适合检查点抑制剂或其他免疫疗法的癌症提供有效的替代方案。