Peer-review started: June 24, 2015
First decision: August 5, 2015
Revised: September 1, 2015
Accepted: October 12, 2015
Article in press: October 13, 2015
Published online: November 27, 2015
Processing time: 156 Days and 14 Hours
Chimeric antigen receptors (CARs) are fusion molecules that may be genetically delivered ex-vivo to T-cells and other immune cell populations, thereby conferring specificity for native target antigens found on the surface of tumour and other target cell types. Antigen recognition by CARs is neither restricted by nor dependent upon human leukocyte antigen antigen expression, favouring widespread use of this technology across transplantation barriers. Signalling is delivered by a designer endodomain that provides a tailored and target-dependent activation signal to polyclonal circulating T-cells. Recent clinical data emphasise the enormous promise of this emerging immunotherapeutic strategy for B-cell malignancy, notably acute lymphoblastic leukaemia. In that context, CARs are generally targeted against the ubiquitous B-cell antigen, CD19. However, CAR T-cell immunotherapy is limited by potential for severe on-target toxicity, notably due to cytokine release syndrome. Furthermore, efficacy in the context of solid tumours remains unproven, owing in part to lack of availability of safe tumour-specific targets, inadequate CAR T-cell homing and hostility of the tumour microenvironment to immune effector deployment. Manufacture and commercial development of this strategy also impose new challenges not encountered with more traditional drug products. Finally, there is increasing interest in the application of this technology to the treatment of non-malignant disease states, such as autoimmunity, chronic infection and in the suppression of allograft rejection. Here, we consider the background and direction of travel of this emerging and highly promising treatment for malignant and other disease types.
Core tip: Adoptive immunotherapy using chimeric antigen receptor-engineered T-cells has been in development for 25 years and, recently, has achieved striking impact in the management of B-cell malignancies. However, the therapy is often accompanied by significant toxicity, in particular cytokine release syndrome. While efficacy in B-cell acute leukaemia provides important clinical proof of concept, this therapy remains unproven in the arena of solid tumours and other disease types. Furthermore, manufacture of cell products is complex and difficult to scale out for widespread clinical use. Significant effort on all of these fronts will be required to enable this promising immunotherapy to enter the therapeutic mainstream.