Shortly, after ipilimumab was approved, the utility of another important immune checkpoint was successfully proven in clinical trials. The programmed death-1 (PD-1) checkpoint, which similar to CTLA-4 serves as a negative regulator of T-cell activity, has been shown to be quite relevant for drug development in melanoma.19–21 Mechanistically, when the PD-1 receptor binds to its ligand (programmed death-ligand 1 receptor [PD-L1]), an inhibitory signal is induced in T cells resulting in anergy and exhaustion. The ligand for PD-1 (PD-L1) is frequently expressed on the surface of melanoma cells and functions to help these cells escape immune surveillance. Two anti-PD-1 antibodies have been extensively studied and now FDA approved in melanoma, nivolumab and pembrolizumab. Blockade of PD-1 with monoclonal antibody allows activation and potentiation of T-cell lymphocytes, which can then result in clinically significant anticancer efficacy. Unique clinical features of both CTLA-4 and PD-1 inhibitor therapies have included the potential for delayed treatment responses (including early progression followed by response), pseudo-progression (tumor size increase due to inflammatory infiltrates), prolonged stable disease. and autoimmune side effects.22Autoimmune side effects that have been observed with both CTLA-4 and PD-1 inhibitions are similar and include fatigue, colitis, dermatitis, hepatitis, and endocrinopathies among many other less common and rare inflammatory toxicities. However, an important distinguishing point between these two forms of immune checkpoint inhibitors is that side effects have tended to be of higher grade and frequency for ipilimumab compared to PD-1 inhibitors alone.

The development of BRAF-targeted therapies and immune checkpoint therapies has revolutionized the treatment landscape for melanoma. In particular, immune checkpoint inhibitors have demonstrated substantial potential for long-term survival in these patients fundamentally changing the field. The focus of this review is on the impact of the PD-1 antibody, pembrolizumab, which has been FDA approved for use in metastatic melanoma and is currently being studied in an array of clinical trials hoping to further advance clinical outcomes.

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PD-1 pathway function

PD-1 and other immune checkpoints play a fundamental role in immune response regulation. As shown in Figure 1, T lymphocytes are initially activated after the T-cell receptor (TCR) on the lymphocyte binds to antigen via the major histocompatibility complex (MHC) on antigen-presenting cells (APCs). In the case of T lymphocytes activated against melanoma cells, the antigen would be a mutated protein produced by the melanoma cell. The activation of the lymphocyte also requires a costimulatory signal such as CD28 (lymphocyte) and B7 (APC). From that point, the lymphocyte’s activity is able to be further fine-tuned by signals from inhibitory and stimulatory immune checkpoint coreceptors expressed on the cell surface that regulate the magnitude and duration of its immune response. There are a variety of immune checkpoints with CTLA-4 and PD-1 being negative regulators of lymphocyte function.23 The potential of the PD-1 receptors as an immune therapeutic target was supported by host of preclinical research. Initial work showed that aged PD-1 knockout mice spontaneously acquired autoimmune disease, providing proof of the receptor’s role in immune response regulation.24 In addition, deficiency of PD-1 in mice enhances cytotoxic CD8 T-cell activity and increased their immune response to viral infection.23

The PD-1 receptor is expressed by activated T cells, natural killer cells, and myeloid cells and has two ligands: PD-L1 (or B7-H1) and PD-L2 (or B7-DC). The PD-1 ligand, PD-L1, varies in expression and location between different cells and is found to be highly expressed on tumor cells and virus-infected cells. Evaluation of PD-1 function in transgenically expressed PD-L1 tumor cells transplanted into mice has shown that, when PD-L1 is highly expressed within the tumor, there is an inhibition of CD8 T-cell-mediated cytotoxicity and promotion of tumor growth.25 This effect was reversed with the use of PD-1 antibody in this model. These findings support that tumors expressing PD-L1 have the potential to escape immune surveillance. Another means by which PD-1 activation can promote a protumor immune environment is the effect on CD28-mediated costimulation. An imbalance of PD-L1 and the costimulatory B7.1 and B7.2 signals on APCs can affect the extent of T-cell activation and lead to a balance between tolerance and autoimmunity.25,26

The binding of PD-1 receptor to one of its two ligands, PD-L1 or PD-L2, results in a series of intracellular events culminating in the inhibition of TCR function and T-cell proliferation, thereby affecting the potential immune response.23 Additionally, activation of the PD-1 receptor by ligand binding affects lymphocyte function through a variety of intracellular pathways including inhibition of cell survival proteins (eg, BCL-2), decreased metabolic activity through downregulation of GLUT-1 transporter proteins, and altered cell cycle progression.27 These biological findings supported PD-1 and the PD-1 ligand as potential targets for immunotherapy drug development.