Clinical applications of PD-1-based therapy: a focus on pembrolizumab (MK-3475) in the management of melanoma and other tumor types

Abstract

Preclinical work has led to an increased understanding of the immunomodulatory mechanisms involved in the regulation of the antitumor response in a variety of tumor types. PD-1 (programmed death 1) appears to be a key checkpoint involved in immune suppression in the tumor microenvironment, even in diseases not previously thought to be sensitive to immune manipulation. More recently, the subsequent clinical development of PD-1-based therapy has resulted in a major breakthrough in the field of oncology. Pembrolizumab, a humanized highly selective IgG4 anti-PD-1 monoclonal antibody, was recently approved for the treatment of advanced melanoma based on promising early-phase clinical data. Encouraging results have also been seen in other malignancies, and PD-1-targeted therapies are likely to markedly change the treatment landscape. Future work will center on rationally designed combination strategies in order to potentiate the antitumor immune response and overcome mechanisms of resistance.

Keywords: PD-1; antitumor activity; cancer; immunotherapy; nivolumab; pembrolizumab.

Figure 1

Overview of the PD-1 pathway. Notes: (A) Binding of PD-1 on the T cell with tumor-associated PD-L1 results in downregulation of T-cell effector functions. (B) Blocking this interaction with an anti-PD-1 antibody prevents this downregulation and restores potential antitumor activity. Abbreviations: MHC, major histocompatibility complex; TCR, T-cell receptor; PD-1, programmed death 1; PD-L1, PD-1 ligand.