Reorienting the immune system in the treatment of cancer by using anti-PD-1 and anti-PD-L1 antibodies

• We review PD-1 pathway blockade in the context of immunotherapy of cancer.
• PD-1 and its ligands are excellent targets in anti-cancer therapy.
• Anti-PD-1 and anti-PD-L1 antibodies have shown promising clinical activity.
• Two anti-PD-1 antibodies are FDA-approved for treatment of metastatic melanoma.
• Combination therapy holds the promise of producing stronger anti-cancer effects.

Physiologically, the programmed death 1 (PD-1) pathway is involved in limiting the killing of bystander cells during an infection and controlling autoimmunity. However, cancers exploit this system to avoid immune killing, and PD-1 ligand 1 and 2 (PD-L1 and PD-L2) expression on tumor cells, as well as PD-1 expression on tumor-infiltrating lymphocytes, have shown to be negative prognostic factors. Promising clinical results have been obtained by PD-1 pathway blockade in a range of cancers while still maintaining a manageable toxicity profile, and two anti-PD-1 antibodies are now approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma. As already shown with nivolumab and ipilimumab, the combination of PD-1 pathway blockade with other anticancer agents holds promise in the form of additive synergistic anticancer effects.