Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

SIMPLE SUMMARY: Novel pharmacological approaches are needed to improve treatments of advanced cancers, despite the considerable benefit of immunotherapy. New drugs are searched for to complement the activity of monoclonal antibodies targeted to the PD-1/PD-L1 immune checkpoint. Here, we have identified and discussed known drugs which could reinforce immunotherapy based on their capacity to modulate this major checkpoint. The repositioning of these drugs, in particular liothyronine, azelnidipine, niclosamide, and albendazole, may represent an alternative approach to improve cancer treatments, compared to the de novo drug design strategy. The repurposing of a few other established drugs to promote cancer immunotherapy is also presented. ABSTRACT: Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer.