Driving CAR T-cells forward

Nature Reviews Clinical Oncology | Review

Driving CAR T-cells forward

Hollie J. Jackson, Sarwish Rafiq & Renier J. Brentjens


Nature Reviews Clinical Oncology
(2016)
doi:10.1038/nrclinonc.2016.36

Published online
22 March 2016



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.


Introduction

Chimeric antigen receptors (CARs) consist of an extracellular antigen-recognition domain, which is usually an antibody single-chain variable fragment (scFv), but can also be a peptide or another protein, linked to an intracellular signalling domain — usually the CD3ζ (CD3 zeta) chain of the T-cell receptor. The extracellular portion of the CAR permits the recognition of a specific antigen by a T cell and, subsequently, the signalling domains stimulate T-cell proliferation, cytolysis and cytokine secretion to eliminate the target cell. The patients' own T cells (or those from an allogeneic donor) are isolated, activated and genetically modified to generate CAR T cells, which are then infused into the same patient. This approach carries a very low risk of graft-versus-host disease and enables lipid, protein and carbohydrate antigens to be targeted by T cells in an MHC-unrestricted fashion. Additionally, one CAR design can be used to treat all cancers expressing the same antigen. The need to generate T cells for each patient was once considered to be a financial and technical obstruction to this therapeutic approach, but the success of CAR-T-cell therapy for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL) has demonstrated that CAR T cells can be produced efficiently and for a reasonable cost.

CD19-targeted CAR T cells have been investigated clinically for the treatment of B-cell malignancies. CD19-targeted CAR-T-cell therapy has repeatedly demonstrated to produce marked antitumour responses in patients with B-ALL1, 2, 3. Following this success, much attention has been devoted to the development of CAR T cells for the successful treatment of other haematological malignancies and solid tumours. In this Review, we discuss successful CD19-targeted CAR-T-cell therapies, CAR-T-cell designs targeting other molecules for the treatment of haematological malignancies, and novel targets proposed for the treatment of solid tumours. This discussion will be limited to approaches with registered clinical trials. In our opinion, the findings from these trials will be instrumental to increase our understanding and optimize the efficacy of this promising cancer treatment.