As a result, PD-1 signaling prevents excessive or harmful inflammation and maintains immune tolerance to self-antigens under normal conditions 10. PD-L1 is often overexpressed in different tumors, and its interaction with PD-1 on T cells enables cancer cells to evade T-cell-mediated immune responses 11. Thus, blocking the PD-1/PD-L1 interaction can restore T-cell activation and antitumor responses 12– 14. The success of antibody-based PD-1/PD-L1 blockade therapies has provided a major breakthrough in the fight against human cancers, especially for solid tumors. The FDA approved the first anti-PD-L1 drug, atezolizumab (Tecentriq®), for the treatment of advanced urothelial carcinoma in May 2016 and metastatic non-small cell lung cancer (NSCLC) in October 2016 15– 18.

In 2017, avelumab (Bavencio®) and durvalumab (Imfinzi®) were also approved by the FDA for Merkel-cell carcinoma and advanced bladder cancer, respectively (Supplementary Table S1). Prior to the approval of the anti-PD-L1 antibodies, the anti-PD-1 drugs pembrolizumab (Keytruda®) and nivolumab (Opdivo®) have been widely used clinically and demonstrated unprecedented therapeutic benefits since 2014 19– 23. In addition, other anti-PD-L1 antibodies including BMS-936559 are in multiple clinical trials for the treatment of NSCLC, renal cell cancer, head and neck cancer, gastric cancer, and other cancers 24– 27.Ĭombinations of anti-PD-1/PD-L1 antibodies with other therapies are being explored as potentially synergistic therapeutic strategies. Among these, the combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies has been the most successful, probably because PD-1/PD-L1 and CTLA-4/B7 interactions play different roles in T-cell immunity 6, 28– 30.

A clinical trial of a combination therapy involving durvalumab and an anti-CTLA-4 antibody, tremelimumab, showed antitumor activity in NSCLC regardless of PD-L1 status, suggesting that this combination has therapeutic potential for patients with PD-L1-negative tumors 31.

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