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

Abstract

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. Chimeric antigen receptor (CAR) T cell therapies have led to on-target, off-tumour toxicity (OTOT) in clinical trials involving patients with solid tumours. Preclinical mouse models might provide inaccurate predictions of OTOT in patients, reflecting the need for better models to perform preclinical safety assessments. Logic-gating circuits and synthetic biology approaches to CAR T cell engineering have demonstrated specificity in mice, although many of these approaches remain untested in clinical studies. Methods of controlling CAR T cell activity and responding to unexpected OTOT have the potential to improve safety after infusion. We advocate for robust preclinical analyses of the risks of OTOT and the implementation of control strategies capable of regulating CAR T cell activity in patients.