T细胞
癌症研究
细胞毒性T细胞
CD8型
汽车T细胞治疗
生物
作者
Ali Can Sahillioglu,Mireille Toebes,Georgi Apriamashvili,Raquel Gomez,Ton N. Schumacher
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2021-06-30
卷期号:9 (9): 999-1007
被引量:3
标识
DOI:10.1158/2326-6066.cir-21-0095
摘要
Adoptive transfer of genetically modified or donor-derived T cells can efficiently eradicate human tumors but is also frequently associated with major toxicity. There are several switches that can be used to kill the infused cell pool in the case of major toxicity, but the irreversible nature of these suicide switches means that the therapeutic effect is lost when they are used. To address this issue, we engineered a small-molecule responsive genetic safety switch that in the absence of drug robustly blocked cytotoxicity and cytokine expression of primary human T cells. Upon administration of drug, T-cell functions were restored in a reversible and titratable manner. We showed that this T-cell switch was universal, as it could be combined with endogenous or transduced T-cell receptors (TCR), as well as chimeric antigen receptors. The modular nature of the Chemically Regulated - SH2-delivered Inhibitory Tail (CRASH-IT) switch concept, in which inhibitory domains are brought to activating immune receptors in a controlled manner, makes it a versatile platform to regulate the activity of cell products that signal through immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors.
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