Driving CAR T-cells forward

Abstract

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.

Figure 1. CAR-T-cell design

All chimeric antigen receptor (CAR) designs contain an antigen-recognition domain and a signalling domain that provides ‘signal 1’ to activate T cells. Only this signalling domain is present in first-generation CARs. By contrast, a co-stimulatory signalling domain that provides ‘signal 2’ is added in second-generation CARs, and in third-generation CARs two co-stimulatory signalling domains are added.

Figure 2. Approaches to improve CAR-T-cell therapy

An overview of the improvements to chimeric antigen receptor (CAR)-T-cell therapy is shown, and clinical trials testing those strategies are indicated in the legend. a | Engineered CAR T cells that secrete pro-inflammatory cytokines (armoured CAR T cells; NCT02498912). b | Dual receptor expression to target tumour cells and convert tumour-derived cytokines into T-cell activators (NCT01818323). c | Using natural killer (NK)-cell-based recognition domains, such as NKG2-D, in CARs (NCT02203825). d | Combination therapy with monoclonal antibodies (mAb) targeting immune-checkpoint inhibitory receptors to relieve immunosuppression (NCT00586391). e | Infusion of two populations of CAR T cells to eradicate B cells and enable increased persistence of tumour-specific CAR T cells by preventing antibody responses against their foreign antigen components (NCT02465983). f | Targeting the tumour vasculature with CAR T cells, such as VEGFR-2-specific CAR T cells NCT01218867. 4αβ, 4αβ chimeric cytokine receptor; CTLA-4, cytotoxic T-lymphocyte-associate antigen-4; T1E28z, T1E28z chimeric antigen receptor; VEGFR-2, vascular endothelial growth factor receptor 2.