Engineering CAR T cell sharpshooters

Approved CAR T-cell therapies have shown remarkable results in patients with certain types of blood cancers.

However, further innovations are needed before the technology can reach its full potential. In principle, CAR T-cell therapies work because they are engineered with a chimeric antigen receptor (CAR) that is designed to recognise a cancer antigen expressed on the surface of that patient’s cancer cells. When the CAR T-cell therapy is administered to the patient, these CAR T-cells coordinate a targeted immune response against the patient’s cancer.

Ideally, the antigen for a traditional CAR T cell (or a T cell) would be universally and homogeneously expressed on cancer cells, but never expressed on healthy cells. In practice, this "perfect" cancer antigen likely does not exist for solid tumors where antigen expression is heterogeneous, and where overlap between antigen expression on cancer and healthy cells is common.

Two acceptable antigen candidates have been identified for blood cancers (CD19 or B-cell maturation antigen). These antigens are highly expressed in some blood cancers, but they are not cancer-specific. Additionally, in an immune evasion strategy, known as antigen loss, some patients who have received approved CAR T-cell therapies relapse because some of their cancer cells either lack or stop expressing the antigen targeted by their CAR T-cell therapy.

Ongoing challenges with CAR T-cell safety and efficacy reflect fundamental limitations of the initial aim of CAR T-cell development – to engineer cancer-targeting T cells that mirror the function of T cells. Now, efforts to develop more targeted and controlled CAR T-cells reflect a new aim: to engineer CAR T-cells with capabilities that give them distinct advantages over T-cells and first-generation CAR T-cell therapies.