CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
驱动 T 细胞进入免疫排斥肿瘤的合成细胞因子回路
英文原题：Synthetic cytokine circuits that drive T cells into immune-excluded tumors.
查看英文原题
Synthetic cytokine circuits that drive T cells into immune-excluded tumors.
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中文摘要
嵌合抗原受体（CAR）T细胞对具有免疫抑制微环境的实体瘤无效。为了克服抑制，我们在T细胞中设计了回路，使肿瘤特异性synNotch受体局部诱导细胞因子IL-2的产生。这些回路有效增强了CAR-T 细胞的浸润和清除免疫排斥肿瘤的能力，且无全身毒性。最有效的IL-2诱导回路以自分泌及T细胞受体（TCR）或CAR非依赖的方式发挥作用，绕过了包括IL-2消耗或TCR信号抑制在内的抑制机制。这些工程化细胞在目标肿瘤中建立立足点，通过合成Notch诱导的IL-2产生，启动CAR介导的T细胞扩增和细胞杀伤。因此，有可能重建合成T细胞回路，激活最终抗肿瘤反应所需的输出，但以规避肿瘤抑制关键点的方式实现。
展开英文摘要原文
Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity.
The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing.
Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
论文信息
- 作者
- Allen GM、Frankel NW、Reddy NR、Bhargava HK、Yoshida MA、Stark SR、Purl M、Lee J
- 单位
- Cell Design Institute; University of California San Francisco, San Francisco, CA 94158, USA.United States
- 期刊
- Science (New York, N.Y.)2022 Dec 16
- 原文标识
- PubMed 36520915 · DOI 10.1126/science.aba1624
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