具有基因修饰的T细胞疗法，在表达对CD19或B细胞成熟抗原（BCMA）具有特异性的嵌合抗原受体（CARs）的情况下，在治疗某些B细胞恶性肿瘤方面获得了批准。 然而，将这些成功案例转化为治疗实体瘤的方案存在各种挑战，包括由于CAR T细胞介导的细胞毒作用导致靶抗原在非恶性组织中引起的临床严重的“靶标准确、非靶标不准确”的毒性反应（OTOT）的风险。 的确，严重的OTOT已经在与实体瘤患者有关的各种CAR T细胞临床试验中观察到，凸显了建立预测、缓解和控制这种效应发生的策略的重要性。 在本文中，我们总结了CAR T细胞治疗实体瘤的OTOT的当前临床证据，并讨论了预测临床OTOT中小鼠的前临床模型的实用性。 然后，我们描述了正在发展的新策略，以改善CAR T细胞在实体瘤中的特异性，特别是目标结合物的亲和力调节、逻辑电路和合成生物学的作用。 此外，我们还强调了在细胞输注后缓解临床OTOT的控制策略，如调控或消除CAR T细胞活性、CAR表达的体外控制以及CAR T细胞的局部输注。 ©2022. Springer Nature 有限公司。

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.© 2022. Springer Nature Limited.