Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

中文翻译：

---

临床前研究表明，Co-STAR 结合了嵌合抗原和 T 细胞受体的优势，用于治疗低抗原密度的肿瘤


两种类型的工程化 T 细胞已成功用于治疗癌症患者，一种具有源自抗体 [嵌合抗原受体 （CAR）] 的抗原识别结构域，另一种源自 T 细胞受体 （TCR）。CAR 使用高亲和力抗原结合结构域和共刺激结构域来诱导 T 细胞活化，但只能与抗原含量相对较高的靶细胞发生反应。TCR 对其抗原的亲和力要低得多，但可以与仅显示少量抗原分子的靶细胞发生反应。在这里，我们描述了一种新型受体，称为 Co-STAR （用于共刺激合成 TCR 和抗原受体），它结合了 CAR 和 TCR 的各个方面。在 Co-STAR 中，TCR 的抗原识别组分被高亲和力抗体片段取代，共刺激由驱动 NF-κB 信号转导的两个模块（MyD88 和 CD40）提供。使用靶向常见人类白细胞抗原 （HLA） 等位基因中呈递的复发性 p53 新抗原的 TCR 模拟抗体片段，我们证明配备 Co-STAR 的 T 细胞比使用传统 CAR 和患者来源的 TCR 改造的 T 细胞更能杀死携带低密度抗原的癌细胞体外。在小鼠模型中，我们表明 Co-STAR 比用 MyD88 和 CD40 共刺激类似修饰的 TCR 介导更稳健的 T 细胞扩增和更持久的肿瘤消退。我们的数据表明，Co-STAR 可能对癌症中的其他肽-HLA 抗原和抗原密度可能限制工程 T 细胞功效的其他靶点具有效用。