肿瘤细胞治疗研究
英文原题：Microenvironment actuated CAR T cells improve solid tumor efficacy without toxicity.
嵌合抗原受体（CAR）T细胞疗法在治疗实体瘤时取得成功的一个主要限制因素是靶向的肿瘤抗原也存在于正常组织上。
嵌合抗原受体（CAR）T细胞疗法治疗实体瘤成功的一个主要限制因素是靶向的肿瘤抗原也存在于正常组织上。针对GD2的CAR T细胞因CAR识别GD2+正常小鼠脑组织而诱导快速、致命的神经毒性。为提高CAR T细胞的选择性，我们设计了一种合成Notch受体，该受体在结合P-选择素（一种在肿瘤新生血管中过表达的细胞黏附蛋白）后选择性表达CAR。这些肿瘤微环境激活的T（MEAT）细胞改善了T细胞在脑内的浸润，在维持抗肿瘤疗效的同时防止了致命性神经毒性。我们发现，条件性CAR表达通过增强MEAT细胞的代谢适应性和输注分化程度较低的产物，改善了TIL（肿瘤浸润淋巴细胞）的持久性。该方法通过将CAR表达及随后的杀伤限制于癌细胞，扩大了可靶向实体瘤抗原的范围，并为其他靶点提供了概念验证模型。
A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2 + normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.
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