Strategies to Address Chimeric Antigen Receptor Tonic Signaling.
Strategies to Address Chimeric Antigen Receptor Tonic Signaling.
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DOI：
10.1158/1535-7163.mct-17-1097
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发表时间：
2018-09
影响因子：
5.7
通讯作者：
Maher J
中科院分区：
文献类型：
--
作者：
Ajina A;Maher J
使用嵌合抗原受体（汽车）的连续性细胞转移已成为复发性或难治性B细胞恶性肿瘤患者最有前途的新治疗方式之一。到目前为止，晚期实体瘤患者的结果令人失望。当部署这些合成融合受体时，在配体不存在的情况下的组成性紧张性信号传导是日益认识到的并发症，并且可能是抗肿瘤功效差、存活受损和体内持久性降低的原因。与此同时，配体依赖性紧张性信号传导可以介导毒性并促进T细胞无反应性、衰竭和活化诱导的细胞死亡。在这里，我们回顾了支持CAR紧张信号传导的机制，并强调了在进行微妙的结构变化或改变CAR转导方法后可能出现的各种各样的影响。我们强调的战略，以防止不受约束的紧张信号，并解决其有害后果。我们还在内源性TCR紧张信号传导的背景下构建了这种现象，其已显示出调节外周耐受性并促进靶向外源抗原，并提出了增选配体依赖性CAR紧张信号传导以促进体内持久性和功效的机会。
Adoptive cell transfer using chimeric antigen receptors (CARs) has emerged as one of the most promising new therapeutic modalities for patients with relapsed or refractory B-cell malignancies. Thus far, results in patients with advanced solid tumours have proven disappointing. Constitutive tonic signalling in the absence of ligand is an increasingly recognised complication when deploying these synthetic fusion receptors and can be a cause of poor anti-tumour efficacy, impaired survival and reduced persistence in vivo. In parallel, ligand-dependent tonic signalling can mediate toxicity and promote T-cell anergy, exhaustion and activation-induced cell death. Here, we review the mechanisms underpinning CAR tonic signalling and highlight the wide variety of effects that can emerge after making subtle structural changes or altering the methodology of CAR transduction. We highlight strategies to prevent unconstrained tonic signalling and address its deleterious consequences. We also frame this phenomenon in the context of endogenous TCR tonic signalling, which has been shown to regulate peripheral tolerance and facilitate the targeting of foreign antigens and suggest opportunities to co-opt ligand-dependent CAR tonic signalling in order to facilitate in vivo persistence and efficacy.