Progress and prospects for engineered T cell therapies

Abstract

Proof-of-concept studies have demonstrated the therapeutic potential of engineered T cells. Transfer of recombinant antigen-specific T cell receptors (TCR) and chimaeric antigen receptors (CARs) against tumour and viral antigens are under investigation by multiple approaches, including viral- and nonviral-mediated gene transfer into both autologous and allogeneic T cell populations. There have been notable successes recently using viral vector-mediated transfer of CARs specific for B cell antigens, but also reports of anticipated and unanticipated complications in these and other studies. We review progress in this promising area of cellular therapy, and consider developments in antigen receptor therapies including the application of emerging gene-editing technologies.

Keywords: T cells; gene therapy; transplantation.

Fig 1

T cells engineered to express antigen-specific receptors can recognize and eliminate leukaemic cells. The αβ T cell receptor (TCR) comprises a heterodimer that can be engineered to prevent cross-pairing with endogenous TCR chains, and is expressed in association with signalling chains of the CD3 complex. TCRs recognize specific antigenic peptides that have been processed and presented in association with human leucocyte antigen (HLA) molecules expressed on the surface of target cells. Chimaeric antigen receptors are hybrid composites derived from the antigen binding domains of antibodies, linked to CD3ζ activation domains and costimulatory moieties via transmembrane bridges. These receptors mediate high affinity binding of target cell surface proteins and are independent of HLA presentation. CAR, chimaeric antigen receptor; MHC, major histocompatibility complex.

Fig 2

Molecular tools for gene editing are evolving and can mediate highly specific cleavage of double stranded DNA at an efficiency that is sufficient to be therapeutically useful. Zinc finger nucleases (ZFNs) are already being evaluated for disruption of the Human immunodeficiency virus co-receptor CCR5 in T cells. In common with alternative reagents based on transcription activator-like effector nucleases (TALENs), scission relies on dimerization of Fok1 endonucleases at defined genomic target sites. Recently, RNA-based DNA targeting reagents called clustered regularly interspaced short palindromic repeats (CRISPRs) have become available, and here, DNA cleavage is mediated by the enzyme Cas9. These reagents open up the possibility of designer T cells with multiple genetic modifications in combination with introduced receptors and safety/selection genes.