Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy

Introduction: Multiple agents targeting the immune "checkpoint" programmed death-1 (PD-1) pathway have demonstrated early evidence of durable clinical activity and an encouraging safety profile in patients with various tumor types, including some cancers, such as non-small-cell lung cancer, historically perceived as non-immunogenic and thus nonresponsive to immunotherapy. Areas covered: Functions of the PD-1 pathway in normal immune responses are reviewed, along with the significance of expression of PD-1 and its ligands in malignant settings. Rationale for the development of PD-1 pathway-targeted therapies and associated clinical data are presented. Finally, efforts to date to identify and develop partner predictive or prognostic biomarkers for these new PD-1 pathway-targeted immunotherapies are discussed. Expert opinion: Rather than targeting the tumor directly, immunotherapies inhibiting PD-1 pathway signaling modulate the antitumor immune response. Indeed, these agents have already demonstrated promising antitumor activity and manageable toxicity in various cancers. If future data continue to support encouraging clinical profiles of anti-PD-1 and anti-programmed death-ligand 1 antibodies, the current paradigm of cancer therapy may shift. In select patient populations (ideally identified by a predictive biomarker), PD-1 pathway-targeted immunotherapy has the potential to serve as the backbone of cancer treatment, and trials evaluating combinations with chemotherapy and/or molecularly targeted therapies will determine whether additive or even synergistic responses can be achieved.