Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

嵌合抗原受体 医学 癌症研究 CD19 抗原 毒性 细胞 免疫疗法 肿瘤科 内科学 免疫学 癌症 生物 遗传学
作者
Christian Flugel,Robbie G. Majzner,Giedre Krenciute,Gianpietro Dotti,Stanley R. Riddell,Dimitrios L. Wagner,Mohamed Abou‐El‐Enein
出处
期刊:Nature Reviews Clinical Oncology [Springer Nature]
卷期号:20 (1): 49-62 被引量:158
标识
DOI:10.1038/s41571-022-00704-3
摘要

Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cell-mediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR T cell clinical trials involving patients with solid tumours, highlighting the importance of establishing strategies to predict, mitigate and control the onset of this effect. In this Review, we summarize current clinical evidence of OTOT with CAR T cells in the treatment of solid tumours and discuss the utility of preclinical mouse models in predicting clinical OTOT. We then describe novel strategies being developed to improve the specificity of CAR T cells in solid tumours, particularly the role of affinity tuning of target binders, logic circuits and synthetic biology. Furthermore, we highlight control strategies that can be used to mitigate clinical OTOT following cell infusion such as regulating or eliminating CAR T cell activity, exogenous control of CAR expression, and local administration of CAR T cells. Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.
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