Tumour-Associated Hypoxia: Can We Give Chimeric Antigen Receptor T Cells More Breathing Space?

Abstract

Immunotherapy using chimeric antigen receptor (CAR)-engineered T cells has encountered important limitations in the transition of their use from liquid to solid tumours. Success is dependent upon T-cell trafficking to, and functional persistence within, tumours that often present a metabolically and immunologically hostile microenvironment. Moreover, CAR targets that are tumour specific are extremely scarce. To address these issues, several strategies have been proposed to improve both tumour selectivity and safety. One approach involves the engineering of CAR-T cells that only deploy their effector function at tumour sites. Conceptually, a solution for this exploits the oxygen-limited nature of advanced tumour deposits through the engineering of CAR that are exclusively expressed or activated under conditions of profound hypoxia. T cells have a complex inter-relationship with oxygen, which also needs to be factored into the refinement of these technologies. Ideally, oxygen-sensing CAR should only function when oxygen tension is below 2%, as is commonly the case in solid tumours but rare in healthy tissue. Successful advancement of such technologies presents opportunities for solid tumour immunotherapy because it should broaden the target repertoire that may safely be exploited in this context.

Keywords

• adoptive cell therapy
• chimeric antigen receptor (car)
• car-t cells
• hypoxiainducible factor-1-α (hif1-α)
• hypoxia-responsive elements (hre)
• hypoxia
• on-target off-tumour
• immunotherapy
• oncology
• oxygen-sensitive car