肿瘤细胞治疗研究
英文原题：An engineering strategy to target activated EGFR with CAR T cells.
嵌合抗原受体（CAR）T细胞在血液系统恶性肿瘤中显示出显著的缓解率。
嵌合抗原受体（CAR）T细胞在血液系统恶性肿瘤中已显示出显著的缓解率。相比之下，CAR T细胞治疗实体瘤面临若干挑战，尤其是大多数肿瘤相关抗原在重要器官中表达水平较低，导致靶向/非肿瘤毒性。因此，迫切需要创新方法来提高CAR T细胞的肿瘤特异性。基于许多人类实体瘤通过分泌EGFR配体激活其表面表皮生长因子受体（EGFR）这一观察，我们开发了一种工程化策略，使CAR结合结构域特异性针对配体激活构象的EGFR。我们在多个实验系统中证明，所生成的结合结构域确实使CAR T细胞能够区分活性和非活性EGFR。我们预期这一工程化概念将成为提高针对EGFR阳性实体癌的CAR T细胞肿瘤特异性的重要一步。
Chimeric antigen receptor (CAR) T cells have shown remarkable response rates in hematological malignancies. In contrast, CAR T cell treatment of solid tumors is associated with several challenges, in particular the expression of most tumor-associated antigens at lower levels in vital organs, resulting in on-target/off-tumor toxicities. Thus, innovative approaches to improve the tumor specificity of CAR T cells are urgently needed. Based on the observation that many human solid tumors activate epidermal growth factor receptor (EGFR) on their surface through secretion of EGFR ligands, we developed an engineering strategy for CAR-binding domains specifically directed against the ligand-activated conformation of EGFR. We show, in several experimental systems, that the generated binding domains indeed enable CAR T cells to distinguish between active and inactive EGFR. We anticipate that this engineering concept will be an important step forward to improve the tumor specificity of CAR T cells directed against EGFR-positive solid cancers.
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