Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Immunol. Nov 27, 2015; 5(3): 86-94
Published online Nov 27, 2015. doi: 10.5411/wji.v5.i3.86
Chimeric antigen receptors: On the road to realising their full potential
May CI van Schalkwyk, John Maher
May CI van Schalkwyk, Department of HIV Medicine, Royal Free Hospital, Royal Free London NHS Foundation Trust, London NW3 2QG, United Kingdom
May CI van Schalkwyk, John Maher, CAR Mechanics Group, Department of Research Oncology, Guy’s Hospital Campus, King’s Health Partners Integrated Cancer Centre, King’s College London, London SE1 9RT, United Kingdom
John Maher, Department of Immunology, Barnet Hospital, Royal Free London NHS Foundation Trust, Hertfordshire EN5 3DJ, United Kingdom
John Maher, Department of Clinical Immunology and Allergy, King’s College Hospital NHS Foundation Trust, London SE5 9RS, United Kingdom
Author contributions: Both authors made an equal contribution to writing of the manuscript.
Supported by The Wellcome Trust, Cancer Research UK, Bayer, the Medical Research Council, Breast Cancer Now, Leukaemia and Lymphoma Research, Worldwide Cancer Research, June Hancock Mesothelioma Foundation, Jon Moulton Charitable Foundation, Pancreatic Cancer United Kingdom, the Experimental Cancer Medicine Centre at King’s College London; and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.
Conflict-of-interest statement: Dr. John Maher is a founder and shareholder in Leucid Bio. There are no other conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. John Maher, CAR Mechanics Group, Department of Research Oncology, Guy’s Hospital Campus, King’s Health Partners Integrated Cancer Centre, King’s College London, Third floor Bermondsey Wing, Great Maze Pond, London SE1 9RT, United Kingdom. john.maher@kcl.ac.uk
Telephone: +44-207-1881468 Fax: +44-207-1880919
Received: June 24, 2015
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
Abstract

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.

Keywords: Adoptive T-cell immunotherapy; Chimeric antigen receptor; Genetic engineering; Leukaemia; Cancer

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.