Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti–PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of “costimulatory bispecifics” that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti–PD-1 approach and endow responsiveness—as well as long-term immune memory—against tumors that otherwise do not respond to anti–PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and “off the shelf” combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.

阻断程序性细胞死亡1（PD-1）检查点的单克隆抗体彻底改变了癌症免疫疗法。但是，许多主要的肿瘤类型仍然对抗PD-1治疗无反应，即使在有反应性的肿瘤类型中，大多数患者仍未产生持久的抗肿瘤免疫力。已经显示双特异性抗体通过使TCR / CD3复合物与肿瘤特异性抗原（TSA）交联来活化T细胞。TSAxCD3双特异性抗体类别在早期临床试验中产生了令人兴奋的结果。我们最近描述了另一类“共刺激双特异性”，其将TSA交叉连接至CD28（TSAxCD28），并与TSAxCD3双特异性协同作用。这里，我们证明，这些TSAxCD28双特异性抗体（一种对前列腺癌具有特异性，另一种对上皮性肿瘤具有特异性）也可以与更广泛的抗PD-1方法协同作用，并赋予反应能力以及长期的免疫记忆，从而对抗那些原本没有的肿瘤仅对抗PD-1有反应。与CD28超激动剂广泛激活T细胞并诱导细胞因子风暴不同，TSAxCD28双特异性抗体在遗传人源化免疫功能小鼠模型中或在灵长类动物中单独使用或与PD-1阻断剂组合使用时几乎没有毒性，甚至没有毒性，因此可能提供良好的耐受性和“现成的”联合疗法与PD-1免疫疗法可以显着增强抗肿瘤功效。