checkpoint

CD47 is the 'don't eat me' signal: it binds SIRP-alpha on macrophages to stop them engulfing the cell, and over 90% of AML blasts and large B-cell lymphoma cells display it. Blocking it should let macrophages eat tumour cells, but red cells carry CD47 too, so anaemia is built in, and the lead antibody magrolimab was dropped after failed trials.

The first immune brake ever targeted for cancer; releasing it won a Nobel Prize and cures a fraction of melanomas.

LAG-3 is the third immune brake to reach approval, combined with PD-1 blockade in melanoma.

PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers.

PD-L1 is the tumour's side of the PD-1 brake, and also the biomarker that decides who gets immunotherapy.

TIGIT is an inhibitory receptor on T and natural killer cells that binds PVR (CD155) on tumour cells, so blocking it was expected to amplify PD-1 and PD-L1 inhibitors. Tiragolumab, domvanalimab and others then failed to add benefit in phase 3 lung cancer trials despite encouraging phase 2 signals, and the lack of a TIGIT-specific biomarker remains a weakness.