Fig. 3. Overcoming on-target, off-tumour toxicities of CAR T cells.
Chimeric antigen receptor (CAR) T cells are typically designed to target tumour-associated antigens (TAAs); however, expression of these antigens on healthy tissues can result in ‘on-target, off-tumour’ CAR T cell-mediated toxicities. A | Engineering strategies aiming to overcome this include mechanisms whereby the tumour specificity of CAR T cells is enhanced by ensuring dependency of functional activation on the recognition of multiple TAAs (a), the absence of an antigen selectively expressed on non-malignant cells (b), or the presence of factors that are typically enriched on tumour cells, such as the phosphoantigens that can be recognized via γδT cell receptors (TCRs) (c), or in the tumour microenvironment (TME) such as the immunosuppressive cytokine IL-4 (d). B | Alternative strategies are based on logic gating and/or conditional expression systems, whereby expression of a CAR targeting a particular TAA is dependent on activation of another engineered transgenic receptor, such as synthetic Notch (synNotch) receptors, by a different TAA (a) or is driven by a factor associated with the TME such as hypoxia (b). C-VHL, HIF1α C-terminal von Hippel–Lindau tumour suppressor protein recognition site; HIF; hypoxia-inducible factor; iCAR, inhibitory chimeric antigen receptor; IL-2Rγ, IL-2 receptor γ chain; IL-4R, IL-4 receptor; IL-7Rα, IL-7 receptor α chain; ITIM, immunoreceptor tyrosine-based inhibitory motif; NTAD, HIF1α N-terminal transactivation domain; N-VHL, HIF1α N-terminal von Hippel–Lindau tumour suppressor protein recognition site; PD-1, programmed cell death 1; STAT5, signal transducer and activator of transcription 5; TH1, T helper 1.