肿瘤细胞治疗研究
英文原题：Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy.
表达嵌合抗原受体的 T 细胞的过继转移在 B 细胞恶性肿瘤中有效。
在 B 细胞恶性肿瘤中，过继转移表达嵌合抗原受体（CAR）的 T 细胞疗法有效。然而，低表达或完全不表达靶抗原的癌细胞可逃避 CAR-T 细胞识别并持续存在，最终导致复发。这些逃逸机制凸显了开发敏感性更高且具多特异性的受体的必要性。研究者提出一种合成嵌合 T 细胞受体（ChTCR），其抗原敏感性优于 CAR 和既往杂合 TCR 设计，并且易于改造成双特异性靶向。ChTCR 模拟天然 TCR 的结构，能够形成经典免疫突触并呈现类 TCR 信号传导。表达双特异性 ChTCR（Bi-ChTCR）的 T 细胞，在雌性小鼠体内清除抗原表达异质性肿瘤的效果优于双特异性 CAR-T 细胞。Bi-ChTCR 架构具有良好适应性，可设计为同时靶向成对的 B 细胞及多发性骨髓瘤抗原。这些发现提供了一种具有广泛适用性的策略，有望应对肿瘤异质性并预防复发。
The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.
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