Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives

Abstract

Engineering T cells with a chimeric antigen receptor (CAR) that reprograms their antigen selectivity and signaling has recently emerged as one of the most promising therapeutic approaches for treating cancers. For example, two CD19-specific CAR T cell (CAR-T) therapies have shown remarkable responses in patients with relapsed/refractory B-cell cancers, and were approved by the US Food and Drug Administration in 2017. This initial clinical success has spurred an explosion of interests in this novel therapy from both academia and industry, and results from basic and clinical research have enabled the rapid evolution of the CAR-T field. In this review, we describe the basic structure of the CAR and discuss how each of its domains affect the efficacy and safety of CAR-T therapies. In addition, we discuss some of the novel concepts and other considerations that are essential for ensuring the future success of CAR-T therapy.

The Application of CAR-T Cells in Haematological Malignancies

“…This region of CAR is called the transmembrane domain and it is the only part of CAR exposed to the hydrophobic environment. Transmembrane domains are frequently derived from CD4, CD8α, or CD28 molecules, similarly to the spacer domains (Lee and Kim 2019). CART characterised by CD3ζ-derived transmembrane domain demonstrate the ability to form complexes with endogenous antigens.…”

“…The binding domain, which is located on the extracellular part of CAR, can recognize surface antigens expressed on target cells (Lee and Kim 2019 ). Effectiveness of antigen recognition depends on the binding affinity determined by the ectodomain of CARs.…”

Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer

“…Initial studies focused on ex-vivo expansion and transplantation of autologous cytotoxic T lymphocytes (CTL) and tumour-infiltrating lymphocytes (TILs) [3,4]. These cells express T cell receptors (TCRs), which recognize peptide-bound major histocompatibility complex (MHC) class I antigens on target cells [5]. However, this strategy is limited by the ability of tumours to downregulate MHC expression or processing of tumour-associated antigens (TAAs), thereby evading CTL detection [4,6,7].…”

“…Chimeric antigen receptors are bespoke fusion molecules that engage native cell surface-associated TAAs without MHC restriction, coupling this to provision of T cell activating and/ or co-stimulatory signals [5,[8][9][10]. Typically, CARs consist of an extracellular (EC) targeting moiety coupled via a spacer and transmembrane (TM) segment to an intracellular (IC) signalling region.…”

“…The greatest clinical impact has been seen with second-generation CARs, in which a single co-stimulatory signalling component, such as CD28 or 4-1BB, is placed upstream of an activating domain [14][15][16]. CAR T cell immunotherapy has achieved remarkable efficacy in relapsed/refractory B cell malignancy, indicated by the approval in multiple territories of two CD19-targeted therapies (Kymriah and Yescarta [5]). Unfortunately, however, this approach has not proved successful for solid tumours, where poor CAR T cell migration and the suppressive tumour microenvironment (TME) hinder efficacy.…”