Abstract
Abstract Metastatic melanoma is a very deadly type of skin cancer with poor prognosis and low 5-year survival rates. Until recently, patients with metastatic melanoma had very few treatment options, which only included dacarbazine and aldesleukin. In 2011, the first checkpoint blocker, ipilimumab was approved for the treatment of unresectable metastatic melanoma but its success was eclipsed by low response rates and high incidence of adverse events. Later in 2014, anti-PD-1 antibodies, nivolumab and pembrolizumab were approved for the treatment of metastatic melanoma. With comparatively high response rates and manageable safety profile, PD-1 blockers were remarkably successful in the treatment of melanoma and also other cancer subtypes such as non-small cell lung cancer and metastatic urothelial carcinoma. This article highlights the success of anti-PD-1 antibodies, discusses the mechanism of PD-1:PD-L1/2 pathway, responses of melanoma patients to PD-1 blockers and the research on improving response rates to PD-1 blockers.
Highlights
Melanoma is a type of skin cancer caused due to uncontrolled proliferation of melanocytes, the melanin producing cells located at the basal layer (Stratum basale) of skin epidermis
In 2014, 3 years after approval of ipilimumab, 2 anti-PD-1 antibodies, pembrolizumab and nivolumab were approved for the treatment of unresectable metastatic melanoma
Combination of anti-CTLA-4 and anti-PD-1 antibodies, approved in 2015 was found to increase the response rates even further and nearly 50% of patients reportedly showed objective responses to therapy [4-6]. This present article discusses the significance of PD-1 blockade in melanoma treatment with details on checkpoint mediated regulation of T-cell activity, functions of PD-1:PD-L pathway, response rates of approved PD-1 blockers including nivolumab and pembrolizumab and details of PD-1:PD-L pathway targeting antibodies in clinical development
Summary
Melanoma is a type of skin cancer caused due to uncontrolled proliferation of melanocytes, the melanin producing cells located at the basal layer (Stratum basale) of skin epidermis. The approval of vemurafenib (BRAFV600E inhibitor) and ipilimumab (anti-CTLA-4 monoclonal antibody) in 2011 was a major milestone in treatment of melanoma as the drugs increased the survival rates of patients and laid foundation for further research in immunotherapy and targeted therapy of melanoma (Figure 1). Combination of anti-CTLA-4 and anti-PD-1 antibodies, approved in 2015 was found to increase the response rates even further and nearly 50% of patients reportedly showed objective responses to therapy [4-6] This present article discusses the significance of PD-1 blockade in melanoma treatment with details on checkpoint mediated regulation of T-cell activity, functions of PD-1:PD-L pathway, response rates of approved PD-1 blockers including nivolumab and pembrolizumab and details of PD-1:PD-L pathway targeting antibodies in clinical development. The cell types expressing PD-1 receptors include activated monocytes, macrophages, myeloid L1
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