Nature Biomedical Engineering ( IF 26.8 ) Pub Date : 2023-06-08 , DOI: 10.1038/s41551-023-01048-8 Angela Q Zhang 1, 2, 3 , Alexander Hostetler 1, 4 , Laura E Chen 1, 4 , Vainavi Mukkamala 1, 4 , Wuhbet Abraham 1 , Lucia T Padilla 1, 4 , Alexandra N Wolff 1, 4 , Laura Maiorino 1 , Coralie M Backlund 1 , Aereas Aung 1 , Mariane Melo 1 , Na Li 1 , Shengwei Wu 1 , Darrell J Irvine 1, 4, 5, 6
The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid–poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, ‘amphiphile tagging’ of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.
中文翻译:
CAR T 细胞通过 CAR 的膜插入配体对实体瘤进行通用重定向
由于肿瘤抗原的异质性表达和健康组织中的靶抗原表达,嵌合抗原受体 (CAR) T 细胞疗法对实体瘤的有效性受到有效靶抗原选择困难的阻碍。在这里,我们表明,具有异硫氰酸荧光素 (FITC) 特异性 CAR 的 T 细胞可以通过肿瘤内施用插入细胞膜的 FITC 偶联脂质-聚(乙烯)-乙二醇两亲性物质来直接对抗实体瘤。在小鼠的同基因和人肿瘤异种移植物中,肿瘤细胞的“两亲性标记”通过肿瘤中 FITC 特异性 CAR T 细胞的增殖和积累来驱动肿瘤消退。在同基因肿瘤中,该疗法诱导宿主 T 细胞浸润,引发内源性肿瘤特异性 T 细胞启动,并导致对远端未治疗肿瘤的活性和防止肿瘤再挑战。用于特定 CAR 的膜插入配体可能促进过继细胞疗法的开发,其作用独立于抗原表达和来源组织。