Teaching an old dog new tricks: next-generation CAR T cells

Abstract

Adoptive T cell therapy (ACT) refers to the therapeutic use of T cells. T cells genetically engineered to express chimeric antigen receptors (CAR) constitute the most clinically advanced form of ACT approved to date for the treatment of CD19-positive leukaemias and lymphomas. CARs are synthetic receptors that are able to confer antigen-binding and activating functions on T cells with the aim of therapeutically targeting cancer cells. Several factors are essential for CAR T cell therapy to be effective, such as recruitment, activation, expansion and persistence of bioengineered T cells at the tumour site. Despite the advances made in CAR T cell therapy, however, most tumour entities still escape immune detection and elimination. A number of strategies counteracting these problems will need to be addressed in order to render T cell therapy effective in more situations than currently possible. Non-haematological tumours are also the subject of active investigation, but ACT has so far shown only marginal success rates in these cases. New approaches are needed to enhance the ability of ACT to target solid tumours without increasing toxicity, by improving recognition, infiltration, and persistence within tumours, as well as an enhanced resistance to the suppressive tumour microenvironment.

Fig. 1

Structure of different chimeric antigen receptor (CAR) generations. a The core structure of a CAR, highlighting the major components of the extracellular domain, the transmembrane domain and the intracellular domain (endodomain). b Evolution of the development of CARs from the first generation, which contained only ITAM motifs in the intracellular domain. Second-generation CARs included one co-stimulatory molecule (CM)1, and third-generation CARs contained a second CM. The fourth generation of CARs was based on second-generation CARs (containing 1–3 ITAMs) paired with a constitutively or inducibly expressed chemokine (e.g. IL-12). These T cells are also referred to as T cell redirected for universal cytokine-mediated killing (TRUCKs). The fifth, or ‘next generation’, is also based on the second generation of CARs, with the addition of intracellular domains of cytokine receptors (e.g. IL-2Rβ chain fragment). ITAM immunoreceptor tyrosine-based activation motifs, CD co-stimulatory domain, IL-12 activation of interleukin 12 transcription, IL-2Rβ truncated intracellular interleukin 2β chain receptor with a STAT3/5 binding motif

Fig. 2

Strategies to address limitations to CAR T cell therapy in solid tumours. Overview of the five major challenges facing adoptive T cell therapy in treating solid tumours—trafficking, proliferation and survival, tumour cell recognition/discrimination, control of transfused T cells and circumventing the immune-suppressive tumour microenvironment—and some approaches currently under investigation to improve them. IL interleukin, VEGFR2 vascular endothelial growth factor receptor 2, Uni-CAR Universal CAR, iCAR inhibitory CAR, TRUCKs T cell redirected for universal cytokine-mediated killing

Fig. 3

Schematic representation of selected strategies to enhance CAR T cells recognition and activation. Recent strategies to enhance the activation of CAR T cells include the use of dual CARs, targeting two surface antigens (a) and split CARs (b). Legend indicated in the figure

Fig. 4

Schematic representation of selected strategies to inhibit CAR T cell activation and prevent off tumour on target activity. Strategies to enhance CAR T cell safety include: a drug-inducible CAR T cells, b CAR T cells that require antigen-specific antibodies (CD16/FITC or Uni-CAR T cells) and c inhibitory CARs (iCARs), which moderate or inhibit T cell activation when antigens expressed on bystander cells are encountered. Legend indicated in the figure