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The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell “dysfunction” or “exhaustion”. While unhelpful ambiguity surrounds the term “dysfunction”, “exhaustion” is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function.

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