Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes

Abstract

Merkel cell carcinoma (MCC) is a rare (∼2,000 U.S. 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 approximately 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, approximately 50% of patients with MCC do not persistently benefit from PD-1 pathway blockade, underscoring the need for novel strategies to broaden antitumor 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. .

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

“…Immunotherapy has revolutionized the therapeutic approach and prognosis of MCC [74]. MCC is characterized by a high recurrence rate even after surgical resection and adjuvant radiotherapy of locoregional disease [75].…”

Skin tumors and their viral origin

“…Recent studies published data which support the anti-PD-L1 antibody -Avelumab's approval in the United States and European Union and use as a standard-of-care treatment for metastatic MCC [55,56]. Detecting the virus presence in a tumor could optimize targeted therapy, such as RB1 tumorsuppressor or NVP-BEZ235, a dual PI3K/mTOR inhibitor [57,58].…”

Second Primary Cancers in Patients with Invasive and In Situ Squamous Cell Skin Carcinoma, Kaposi Sarcoma, and Merkel Cell Carcinoma: Role for Immune Mechanisms?

“…As immunosuppression is the shared risk factor for SCC skin cancer, KS, and MCC, we expect our results to be highly informative concerning immune mechanisms in SPCs (Harms et al, 2018;IARC, 2012a;Rama and Grinyó , 2010;Rangwala and Tsai, 2011). Recent data also suggest that these cancers are responsive to immunotherapy (Colunga et al, 2018;Galanina et al, 2018;Migden et al, 2018). We utilized data from the nationwide Swedish Cancer Registry covering the years 1958 through to 2015.…”