Strategies for Improving the Efficacy of CAR T Cells in Solid Cancers

SIMPLE SUMMARY: Cell therapy with genetically retargeted T cells shows strong clinical efficacy against leukaemia and lymphoma. To make this therapy efficient against solid cancers, a series of hurdles must be addressed. This includes the need to enable the T cells to survive long term in patients and to overcome immunosuppressive mechanisms in the tumour. Further, it is essential to prevent tumour cells from escaping by losing the protein that is recognised by the infused cells. The present article provides an overview of the key strategies that are currently being investigated to overcome these hurdles. A series of approaches have been described in preclinical models, but these remain untested in patients. The further progress of the field will depend on evaluating more strategies in a proper clinical setting. ABSTRACT: Therapy with T cells equipped with chimeric antigen receptors (CARs) shows strong efficacy against leukaemia and lymphoma, but not yet against solid cancers. This has been attributed to insufficient T cell persistence, tumour heterogeneity and an immunosuppressive tumour microenvironment. The present article provides an overview of key strategies that are currently investigated to overcome these hurdles. Basic aspects of CAR design are revisited, relevant for tuning the stimulatory signal to the requirements of solid tumours. Novel approaches for enhancing T cell persistence are highlighted, based on epigenetic or post-translational modifications. Further, the article describes CAR T strategies that are being developed for overcoming tumour heterogeneity and the escape of cancer stem cells, as well as for countering prevalent mechanisms of immune suppression in solid cancers. In general, personalised medicine is faced with a lack of drugs matching the patient’s profile. The advances and flexibility of modern gene engineering may allow for the filling of some of these gaps with tailored CAR T approaches addressing mechanisms identified as important in the individual patient. At this point, however, CAR T cell therapy remains unproved in solid cancers. The further progress of the field will depend on bringing novel strategies into clinical evaluation, while maintaining safety.