期刊
MOLECULAR CANCER THERAPEUTICS
卷 17, 期 9, 页码 1795-1815出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-17-1097
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资金
- Medical Research Council [MR/R001936/1, MR/M024733/1]
- Wellcome Trust [104802/Z/14/Z]
- Cancer Research UK [C11499/A21623]
- British Lung Foundation [MPG16-6]
- Pancreatic Cancer UK
- Experimental Cancer Medicine Centre at King's College London
- King's Health Partners Cancer Research UK Cancer Centre
- National Institute for Health Research (NIHR) Biomedical Research Centre
- MRC [MR/M024733/1, MR/R001936/1] Funding Source: UKRI
- Wellcome Trust [104802/Z/14/Z] Funding Source: Wellcome Trust
Adoptive cell transfer using chimeric antigen receptors (CAR) 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 tumors have proven disappointing. Constitutive tonic signaling in the absence of ligand is an increasingly recognized complication when deploying these synthetic fusion receptors and can be a cause of poor antitumor efficacy, impaired survival, and reduced persistence in vivo. In parallel, ligand-dependent tonic signaling can mediate toxicity and promote T-cell anergy, exhaustion, and activation-induced cell death. Here, we review the mechanisms underpinning CAR tonic signaling 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 signaling and address its deleterious consequences. We also frame this phenomenon in the context of endogenous TCR tonic signaling, which has been shown to regulate peripheral tolerance, facilitate the targeting of foreign antigens, and suggest opportunities to coopt ligand-dependent CAR tonic signaling to facilitate in vivo persistence and efficacy. (C) 2018 AACR.
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