The Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma

Abstract

Purpose Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune-checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non–small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma. Methods PubMed was searched to identify relevant clinical studies of PD-1/PD-L1–targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic. Findings The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management. Implications This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, educati...

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

“…PD-L1 expression on tumor cells is a suggestive, but inadequate, predictive biomarker of response to immune-checkpoint blockade (31), suggesting that PD-L1 expressed by other cells might also be a relevant target for therapy with these agents. It is conceivable that the blockade of PD-L1 on NK cells could be part of the mechanism of action of these Abs, through disruption of the regulatory interaction between NK cells and DCs, which could contribute to the more robust and efficient antitumor CD8 + T cell response seen with anti-PD-1.…”

“…Programmed death ligand 1 (PD-L1), an inhibitory molecule frequently upregulated on tumor cells, is one of the major immunological checkpoints contributing to tumor-immune escape (28) through the inhibition of T cell activation and promotion of apoptosis of DCs (29) and CD8 + T cells (30). In several clinical trials, blockade of programmed death-1 (PD-1) or PD-L1 resulted in enhanced T cell function and improved immune-mediated tumor control (31). PD-L1 is expressed not only by tumor cells but also by tumor-infiltrating immune cells (32), and it has been shown that some patients with PD-L1 2 tumors can also respond to treatment (33).…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…38,44 The extent to which "false negative" classification, due to heterogeneous expression in metastases, accounts for these observed responses is unclear. Further, the baseline levels of expression of PD-L1 by tumor cells or immune cells may have a prognostic value independent of the likelihood of response to therapy, and this needs to be clarified in order to understand how the baseline features may interact with the predictive value of the expression.…”

Relationship between expression of PD-L1 and PD-L2 on esophageal squamous cell carcinoma and the antitumor effects of CD8+ T cells

“…Recently, aberrant PD-L1 and PD-L2 expression by cancer cells has been reported in many human malignancies (17)(18)(19). A series of clinical trials concerning the systemic administration of therapeutic antibodies for blocking PD-1 or PD-L1 have shown a promising clinical effect in various tumors (20,21).…”