Immune checkpoint inhibitors

Checkpoint inhibitors block the immune system's natural "brakes" — checkpoint proteins such as PD-1, PD-L1 and CTLA-4 — which tumours exploit to switch off T cells, restoring the immune system's ability to attack the cancer. They are approved for a wide range of cancers, including melanoma, lung, kidney and bladder cancer and Hodgkin lymphoma, as well as solid tumours defined by DNA-repair defects rather than by location. Typical side effects are rash, diarrhoea and fatigue; less often, the unleashed immune response can inflame healthy organs.

How it works

Immune checkpoints are a normal safety mechanism: proteins on the surface of T cells (such as PD-1 or CTLA-4) bind partner proteins on other cells and deliver an "off" signal that protects healthy tissue from an excessive immune response. Many tumours abuse this mechanism — for example, they produce large amounts of PD-L1, the partner protein of PD-1 — so T cells that reach the tumour are switched off before they can act. Checkpoint inhibitors are antibodies that block this binding between checkpoint proteins and their partners, so the "off" signal is never delivered and T cells keep their ability to kill tumour cells. Because the released brake acts on the whole immune system, the same mechanism can cause immune-related side effects — from common ones such as rash, diarrhoea and fatigue to rarer inflammation of the lungs, bowel, liver, endocrine glands, heart or nervous system, which requires prompt medical attention.