Overexpressed tumor associated antigens (e.g. HER2 and EGFR) are attractive targets for therapeutic T cells, but toxic cross-reaction with normal tissues expressing low antigen levels has been observed with Chimeric Antigen Receptor (CAR) T cells targeting such antigens. Inspired by natural ultrasensitive response circuits, we engineer a two-step positive feedback circuit that allows T cells to discriminate targets based on a sigmoidal antigen density threshold. In this circuit, a low affinity SynNotch receptor for HER2 controls the expression of a high affinity CAR for HER2. Increasing HER2 density thus has cooperative effects on T cells -- it both increases CAR expression and activation -- leading to a sigmoidal response. T Cells with this circuit show sharp discrimination between target cells expressing normal and disease levels of HER2, both in vitro and in vivo.

中文翻译：

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T细胞回路以超灵敏的阈值感应抗原密度

过度表达的肿瘤相关抗原（例如HER2和EGFR）是治疗性T细胞的诱人靶标，但是针对这种抗原的嵌合抗原受体（CAR）T细胞已观察到与表达低抗原水平的正常组织的毒性交叉反应。受自然超敏反应电路的启发，我们设计了两步正反馈电路，该电路使T细胞能够根据S型抗原密度阈值来区分靶标。在该电路中，HER2的低亲和力SynNotch受体控制HER2的高亲和力CAR的表达。因此，增加HER2密度对T细胞具有协同作用-既增加了CAR表达，又激活了-导致了乙状结肠反应。具有此电路的T细胞在表达正常水平和疾病水平的HER2的靶细胞之间表现出明显的区别，