肿瘤细胞治疗研究
英文原题：HLA-independent T cell receptors for targeting tumors with low antigen density.
嵌合抗原受体（CARs）是指引强效免疫反应的抗原受体。
嵌合抗原受体（CAR）是能引导强效免疫应答的抗原受体。与靶抗原低表达相关的肿瘤逃逸正逐渐成为其疗效的一个潜在限制。在此，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复合物来识别细胞表面靶点，该复合物经过重新配置，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HLA的T细胞受体（HIT受体）始终能提供高抗原敏感性，并介导超出基于CD28的CAR（迄今为止最敏感的设计）所能提供的肿瘤识别能力。我们证明，HIT T细胞的功能持久性可通过CD80和4-1BBL的组成性共表达而增强。最后，我们在B细胞白血病和急性髓系白血病的异种移植小鼠模型中，分别靶向CD19和CD70，验证了HIT受体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。
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.
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