For decades, cancer treatment has involved various permutations of three modalities: chemotherapy, surgery and radiotherapy. While these remain the backbone of current protocols, over the last decade, new treatments have emerged with the promise of improving outcomes and quality of life for patients with previously incurable cancers. Immunotherapy, voted ‘breakthrough of the year’ by the journal Science in 2013,1 is one key example that has already impacted the lives of some children with cancer. The term immunotherapy encompasses all treatments that harness the immune system of the host to attack malignant cells such as monoclonal antibodies, checkpoint inhibitors, cancer vaccines, oncolytic viruses, cytokines and chimeric antigen receptor T-cell (CAR T-cell) therapy.2 These therapies have demonstrated their ability to eradicate cancer cells and generate long-lasting responses in human patients, rightly earning their position as the fourth discipline in cancer treatment.3 CAR T-cell therapy has gained significant attention and represents hope for many patients following remarkable successes in curing heavily pretreated paediatric patients with B-cell acute lymphoblastic leukaemia (ALL).4 The clinical applications of CAR T-cell therapy are expanding to solid tumours of childhood; therefore, it is valuable for clinicians who care for children with cancer to understand the principles of this novel therapy.

CAR T-cells are genetically engineered T-cells that express proteins on their surface called chimeric antigen receptors (CARs, figure 1). Classic T-cell activation requires multiple signals. First, an antigen is recognised by the T-cell receptor as peptide bound to proteins encoded by the major histocompatibility complex (MHC). Subsequently, the level of T-cell activation is controlled by interaction of different co-stimulatory receptors such as CD28 and cytokine signalling.5 Cancer cells frequently downregulate MHC expression to avoid T-cell recognition and immune-mediated killing. CAR T-cells, on the other hand, recognise and bind directly to specific antigens on the …