Abstract
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.
Highlights
Introduction to Chimeric Antigen Receptor TechnologyTumour immunotherapy is one of the oldest branches of clinical immunology and has a long but checkered history
This paper considers several aspects of the pre-clinical and clinical development of Chimeric antigen receptor- (CAR-)based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies
The potentiating action of constitutive IL-12 expression upon CAR T cell function was sufficiently potent in one study that the need for lymphodepletion was circumvented by this approach [76]
Summary
Tumour immunotherapy is one of the oldest branches of clinical immunology and has a long but checkered history. A defining property of this technology is the fact that, unlike αβ T cell receptors (TCR), antigen recognition by CARs is direct and is generally not restricted by polymorphic presenting elements such as human leukocyte antigens (HLAs) Advantages of such an immunotherapeutic targeting strategy are threefold. The birth of CAR technology occurred 25 years ago when it was shown that antibody variable light (VL) or heavy (VH ) gene segments can transfer specificity for native antigen, when substituted for the corresponding elements within a TCR αβ heterodimer [7] It was Eshhar who realized the translational potential of such non-HLA-restricted T cell recognition [8, 9]. T cell specificity could be effectively redirected using a single receptor dimer [10]
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