Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies. 1. Introduction to Chimeric Antigen Receptor Technology Tumour immunotherapy is one of the oldest branches of clinical immunology and has a long but checkered history. The overriding goal is to deploy the multiplicity of available immune effector mechanisms against tumour cells, but not against healthy counterparts. Unfortunately however, several obstacles render this a very difficult goal. Although hundreds of so-called tumour antigens have been identified, these are generally derived from self and thus are poorly immunogenic. Furthermore, tumours use several mechanisms to render themselves hostile to the initiation and propagation of immune attack. These immune subversive strategies include reduced expression of HLA molecules and target antigens coupled with the establishment of a microenvironment in which inhibitory cytokines and leukocytes abound (recently reviewed in [1]). Indeed, cancer cells can even dedifferentiate to evade detection in response to inflammatory cues provided by tumour-specific T cells [2]. Consequently, it is not surprising that attempts to harness tumour-specific T cells using a succession of vaccination-based approaches have not achieved striking success [3]. Recent developments using genetically enhanced T cells have led to renewed optimism in the quest to launch immune attack against malignant disease. One increasingly prominent technology in this arena involves the use of the so-called chimeric antigen receptors, or CARs. These bespoke fusion receptors are engineered as chimeric cDNAs
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