Abstract
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with rising incidence and high mortality. Approximately 80% of the cases are caused by the human Merkel cell polyomavirus, while the remaining 20% are induced by UV light leading to mutations. The standard treatment of metastatic MCC is the use of anti-PD-1/-PD-L1-immune checkpoint inhibitors (ICI) such as Pembrolizumab or Avelumab, which in comparison with conventional chemotherapy show better overall response rates and longer duration of responses in patients. Nevertheless, 50% of the patients do not respond or develop ICI-induced, immune-related adverse events (irAEs), due to diverse mechanisms, such as down-regulation of MHC complexes or the induction of anti-inflammatory cytokines. Other immunotherapeutic options such as cytokines and pro-inflammatory agents or the use of therapeutic vaccination offer great ameliorations to ICI. Cytotoxic T-cells play a major role in the effectiveness of ICI, and tumour-infiltrating CD8+ T-cells and their phenotype contribute to the clinical outcome. This literature review presents a summary of current and future checkpoint inhibitor therapies in MCC and demonstrates alternative therapeutic options. Moreover, the importance of T-cell responses and their beneficial role in MCC treatment is discussed.
Highlights
Erlangen-Nürnberg, Hartmannstraße 14, 91052 Erlangen, Germany; Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC early region (ER)-EMN), Östliche Stadtmauerstraße 30, 91054 Erlangen, Germany
Even though the response rates of immune checkpoint inhibitors (ICI) are quite good in Merkel cell carcinoma (MCC), still 50% of patients do not respond to the treatment due to possible resistances which can be either primary, i.e., from the beginning of the treatment or secondary, i.e., when a tumour first responds but later the treatment stops working and the patients relapse
The first trial of that kind was reported by Weide et al investigating the response to an mRNA vaccine, encoding for different melanoma specific antigens injected in 21 metastatic melanoma patients (NCT01684241)
Summary
Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin malignancy. It was first described as a “trabecular carcinoma of the skin” in 1972 by Cyril Toker [1]. Paulson et al showed that the 3-year survival rate in immune-competent patients is twice as high as in immunecompromised patients [22] This suggests that a functional immune system plays a very important role in keeping the tumour under control. Advanced age, as another risk factor, leads to immune senescence, an age-related alteration of the immune system and a loss of T-cell receptor repertoire [23]. As another risk factor, leads to immune senescence, an age-related alteration of the immune system and a loss of T-cell receptor repertoire [23] This could explain the increased incidence of MCC in elderly people. In comparison to the non-viral MCC, the viral MCC does not have this UV-mutational signature and a low TMB [24]
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