checkpoint inhibitor
A checkpoint inhibitor is an immunotherapy that takes the brakes off the immune system so it can attack a tumor. The body's T cells are powerful cancer-killers, but they carry built-in safety switches — checkpoints — that normally stop them from running amok and attacking healthy tissue. Many tumors abuse these switches, pressing the off-button to make themselves invisible. A checkpoint inhibitor jams that off-button so the T cells can do their job.
Mechanistically these drugs are antibodies that bind to a checkpoint protein — such as PD-1 on the T cell, its partner PD-L1 on the tumor, or CTLA-4 — and physically block the handshake that would tell the T cell to stand down. With the inhibitory signal interrupted, T cells that recognize the cancer stay switched on and mount a sustained assault. Unusually for cancer drugs, the target is the patient's own immune cells, not the tumor itself.
Checkpoint inhibitors can produce remarkably durable remissions in cancers once considered untreatable, but only a fraction of patients respond, and predicting who will is imperfect. Because the drug loosens immune restraint everywhere, it can let the immune system attack normal organs, causing autoimmune-like side effects ranging from rashes to serious inflammation of the gut, liver, lungs, or endocrine glands.
Pembrolizumab and nivolumab are antibodies that block PD-1, while ipilimumab blocks CTLA-4 — each freeing T cells to recognize and kill tumor cells.
Antibodies that release different T-cell checkpoints.
Checkpoint inhibitors are antibodies, a biologic modality, so they differ from the small-molecule targeted drugs that dominate this field. They release a brake rather than directly killing cancer cells.