Review ArticleThe Next Immune-Checkpoint Inhibitors: PD-1/PD-L1 Blockade in Melanoma
Introduction
For decades, research has attempted to stimulate an antitumor immune response to fight cancer. However, there are inhibitory pathways that regulate the function of T lymphocytes and cause these attempts to be generally unsuccessful. These “immune checkpoints” not only normally function to control excessive immune activation but also appear to be a means by which tumors evade the immune system. Blockade of these immune checkpoints, such as with programmed cell death (PD)-1 protein and one of its ligands, PD-L1 (also known at B7-H1 and CD274), has demonstrated clinical activity in several types of solid tumors.1, 2, 3, 4, 5 Much of the preclinical and clinical benefit has been described in melanoma.
Metastatic melanoma is an aggressive disease with a 16% 5-year survival rate and responds poorly to most standard chemotherapies.6 Over 80% of cases of melanoma are localized. Yet patients with regional lymph node involvement have a high rate of recurrence, and the number of deaths from this disease per 100,000 persons has remained stable between 1992 and 2011. Interferon and interleukin (IL)-2 have both been approved by the US Food and Drug Administration for the treatment of melanoma.7, 8 Both mediate their benefit by stimulating an antitumor immune response. However, toxicity and low response rates have limited their use significantly. The first immune-checkpoint inhibitor approved by the US Food and Drug Administration (FDA) was ipilimumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody (mAb) that blocks cytotoxic T-lymphocyte antigen (CTLA)-4 for the treatment of metastatic melanoma in 2011.9 Although not yet compared in a randomized clinical trial, ipilimumab is generally considered more tolerable than high-dose IL-2. Both have promising durable response in melanoma.10 Of note, the response rate of ipilimumab may be less than that cited for IL-2.11, 12 A recent follow up of 1861 melanoma patients treated with ipilimumab showed that about 20% survived 3 years but most impressively, at this time the survival curve flattens and most patients alive at 3 years are alive up to 10 years after therapy has been completed.10 Atypical patterns of tumor response to immunotherapies, including ipilimumab, make comparisons of response rates less informative; thus, milestone survival (for example, at 3 years) may be a more appropriate measure of response to immunotherapy.13
With the promising tolerability and efficacy seen with PD-1/PD-L1 checkpoint inhibitors in Phase I/II trials, multiple Phase III clinical trials have opened. A Phase III trial that compared nivolumab and dacarbazine reported better overall survival in the nivolumab arm and was stopped early to allow chemotherapy-treated patients to cross over to PD-1 blockade.14 Currently, nivolumab is being compared to ipilimumab in metastatic melanoma in a Phase III trial. PD-1 pathway blockade has become a major focus in anticancer drug development beyond melanoma. In addition to benefiting patients with renal cell carcinoma, it has reported benefit in patients with tumors previously not considered sensitive to immunotherapies, including non–small cell lung cancer. This finding has stimulated the investigation of numerous combinations in ongoing Phase I and II trials. While immunotherapy combinations often have been limited by their toxicity, ipilimumab + nivolumab was the first reported checkpoint-inhibitor combination and has been associated with response in melanoma.5 Given the tolerability of many of the PD-1 pathway inhibitors, these combination regimens will likely play a major role in the future of immune-checkpoint blockade in oncology.5 The current goal is to find the treatment with the best balance of high efficacy and low toxicity.
Section snippets
Materials and Methods
PubMed was searched for articles published before July 1, 2014, using the search terms PD-1 AND melanoma and PD-L1 AND melanoma. This key-word search yielded 171 and 119 references, respectively, totaling 207 nonduplicate references. In a PubMed search of clinical trials containing the terms PD-1 and PD-L1, there were 11 publications. These publications were reviewed, as were additional publications referenced. The clinicaltrial.gov database was searched for interventional trials of PD-1 or
Role of PD-1 Pathway in Tolerance and Chronic Infection
PD-1 was originally isolated from a T-cell hybridoma undergoing T-cell receptor activation–induced cell death, hence its name, programmed death 1.15 Despite its name, PD-1 does not appear to directly engage a cell-death pathway like CD95, but indirectly effects cell death through diminished cell growth factors and survival signals. The interaction between PD-1 and its ligands PD-L1 and PD-L2 reduces T-lymphocyte function (Figure 1).16 PD-1 signaling inhibits T-cell activation, leading to
Discussion
Immune-checkpoint blockade has been reported to have antitumor effects with multiple agents in a wide variety of Phase I, II, and III clinical trials. With accelerated approval of pembrolizumab and nivolumab, it is essential to realize that vigilance is required in the Phase IV setting. Despite nivolumab not being FDA approved for the treatment of melanoma before ipilimumab, with the positive results of the Phase III trial that compared nivolumab to chemotherapy in previously untreated patients
Conclusions
This family of immune-checkpoint inhibitors not only benefits patients with metastatic melanoma, but also historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has shown 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,
Conflicts of Interest
Dr. Freeman holds patents, and receives patent royalties from, on the PD-1 pathway from Bristol-Myers Squibb, Roche, Merck, EMD-Serono, Boehringer-Ingelheim, Amplimmune, and Novartis. Dr. McDermott has served on the advisory boards of Genentech, Bristol-Myers Squibb, Merck, and Prometheus. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
Acknowledgments
This research was financially supported by a grant from the National Institutes of Health–National Cancer Institute (P50CA101942; BIDMC); the Claudia Adams Barr Program for Innovative Cancer Research; an American Association for Cancer Research Basic Cancer Research Fellowship (14-40-01-MAHO); the American Society of Clinical Oncology Young Investigator Award from the Kidney Cancer Association (to K.M.); and grants U54CA163125, P01AI054456, U54CA16312, and R01AI089955 (to G.J.F.; DFCI).
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