PD-1 and PD-L1 antibodies in cancer: current status and future directions

Abstract

Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.

Keywords: Biomarkers; Checkpoint inhibitors; Immunotherapy; Microbiome; PD-1; PD-L1.