Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates

Abstract

Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors—avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab—have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

Current Progress in Vaccines against Merkel Cell Carcinoma: A Narrative Review and Update

“…Potential side effects could be similar to those seen with combination immunotherapy, such as nivolumab and ipilimumab. These include autoimmune hypophysitis, thyroiditis, autoimmune colitis, and autoimmune hepatitis, particularly as we are dealing in MCC with a high-aged population [43]. Severe side effects such as cytokine release syndrome, which can be life-threatening, are also possible.…”

“…Hence, MCCs of both etiologies should express potential immunogenic antigens, i.e., viral peptides in the case of virus-positive MCC. In the case of MCPyV-negative MCC, neoantigens (aberrant proteins) that develop due to mutations in the tumor represent potential immunogenic agents [43]. The biological behavior of MCC is highly aggressive, with high rates of local recurrences, regional lymph node, and distant metastasis.…”

“…The biological behavior of MCC is highly aggressive, with high rates of local recurrences, regional lymph node, and distant metastasis. Hence, the 5-year relative survival estimates from population-based registries (US, Netherlands, Finland, Spain, Germany, and New Zealand) range from 36% to 65% for men and for women 47% to 84% [43]. When compared to the chemotherapy era, the management of advanced MCC has been significantly improved since the introduction of immunotherapy, particularly using immune checkpoint inhibitors (ICI).…”

“…Given the general success of immunotherapy in MCC and the expression of a necessary viral protein shared by virus-positive cases, this tumor is a prime candidate for vaccination strategies. Consequently, the development of virus-directed vaccines against MCC has significantly increased in recent years [7,[43][44][45][46][47][48][49][50][51]. For example, peptide-and DNA-based vaccines and combination therapies with vaccines and ICI are currently being investigated for treatment of MCC in preclinical and clinical trials.…”

Incidence and Relative Survival of Patients with Merkel Cell Carcinoma in North Rhine-Westphalia, Germany, 2008–2021

“…Moreover, ICIs have revolutionized the treatment landscape for advanced MCC. Indeed, immunotherapy has become the preferred first-line treatment for advanced MCC due to its improved efficacy and durability of responses compared with chemotherapy [ 5 ].…”