肿瘤细胞治疗研究
英文原题：Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors.
Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors.
CAR-T 细胞用于治疗实体瘤时经常面临重大挑战，主要原因是肿瘤抗原的异质性。
实体瘤嵌合抗原受体（CAR）T 细胞治疗常因肿瘤抗原异质性而面临显著挑战。本研究评估一种酸性靶向过渡辅助通用 CAR-T（ATT-CAR-T）策略的疗效，该策略借助酸性靶向过渡实现作用。具体而言，将 EGFRvIII 肽连接于低 pH 插入肽（pHLIP）的 N 端。肿瘤微环境的酸性条件触发该肽结构改变，使其选择性整合至实体瘤细胞膜中。酸性靶向过渡组分可将 EGFRvIII 肽重定位至不同肿瘤细胞膜，从而使 EGFRvIII 特异性 CAR-T 直接清除这些细胞；即便肿瘤缺乏内源性抗原，该方法仍然有效。体内实验显示，该组分可在酸性肿瘤微环境中显著修饰抗原。将该组分与 CAR-T 结合，在抗击实体瘤方面疗效显著。结果表明，ATT-CAR-T 可应对肿瘤异质性挑战，拓展 CAR-T 治疗实体瘤的应用。
The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors.
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