Merkel cell carcinoma in the age of immunotherapy: Facts and hopes

Merkel cell carcinoma (MCC) is a rare (~2,000 US cases/year) but aggressive neuroendocrine tumor of the skin. For advanced MCC, cytotoxic chemotherapy only infrequently (<10% of cases) offers durable clinical responses (>1 year) suggesting a great need for improved therapeutic options. In 2008, the Merkel cell polyomavirus (MCPyV) was discovered and is clonally integrated in ~80% of MCC tumors. The remaining 20% of MCC tumors have large numbers of UV-associated mutations. Importantly, both the UV-induced-neoantigens in virus-negative tumors and the MCPyV T antigen oncogenes that are required for virus-positive tumor growth are immunogenic. Indeed, antigen-specific T cells detected in patients are frequently dysfunctional/'exhausted' and the inhibitory ligand, PD-L1, is often present in MCC tumors. These findings led to recent clinical trials involving PD-1 pathway blockade in advanced MCC. The combined data from these trials, involving three PD-1 pathway blocking agents (avelumab, pembrolizumab, and nivolumab) indicated a high frequency of durable responses in treated patients. Of note, prior treatment with chemotherapy was associated with decreased response rates to PD-1 checkpoint blockade. Over the past year, these striking data led to major changes in advanced MCC therapy, including the first-ever FDA drug approval for this disease. Despite these successes, ~50% of MCC patients do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden anti-tumor immune responses in these patients. Here we highlight recent progress in MCC including the underlying mechanisms of immune evasion and emerging approaches to augment the efficacy of PD-1 pathway blockade.

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