Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAC locus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor–CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

嵌合抗原受体 (CAR) 是指导有效免疫反应的抗原受体。与低靶抗原表达相关的肿瘤逃逸正在成为其功效的潜在限制之一。在这里，我们编辑人外周血 T 细胞中的 TRAC 基因座，通过其 T 细胞受体 CD3 复合物来接合细胞表面靶标，该复合物重新配置为利用与匹配的 CAR 相同的免疫球蛋白重链和轻链。我们证明，这些不依赖于 HLA 的 T 细胞受体（HIT 受体）始终能够提供高抗原敏感性并介导肿瘤识别，超出了基于 CD28 的 CAR（迄今为止最敏感的设计）所能提供的功能。我们证明，CD80 和 4-1BBL 的组成型共表达可以增强 HIT T 细胞的功能持久性。最后，我们验证了 HIT 受体在 B 细胞白血病和急性髓系白血病异种移植小鼠模型中分别针对 CD19 和 CD70 所提供的抗原敏感性增加。总体而言，HIT 受体非常适合靶向低丰度的细胞表面抗原。