Multimodal Strategy in Localized Merkel Cell Carcinoma: Where Are We and Where Are We Heading?

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin whose incidence is rising. Multimodal treatment is crucial in the non-metastatic, potentially curable setting. However, the optimal management of patients with non-metastatic MCC is still unclear. In addition, novel insights into tumor biology and newly developed treatments (e.g., immune checkpoint inhibitors) that dramatically improved outcomes in the advanced setting are being investigated in earlier stages with promising results. Nevertheless, the combination of new strategies with consolidated ones needs to be clarified. We reviewed available evidence supporting the current treatment recommendations of localized MCC with a focus on potentially ground-breaking future strategies. Advantages and disadvantages of the different treatment modalities, including surgery, radiotherapy, chemotherapy, and immunotherapy in the non-metastatic setting, are analyzed, as well as those of different treatment modalities (adjuvant as opposed to neoadjuvant). Lastly, we provide an outlook of remarkable ongoing studies and of promising agents and strategies in the treatment of patients with non-metastatic MCC.

Cutaneous metastases: From epidemiology to therapy

“…Clinical trials are currently underway to investigate vaccines in metastatic or locally advanced Merkel cell carcinoma (NCT04160065, NCT04246671). Interestingly, IFx‐Hu2.0 is an experimental intralesional vaccine inducing the expression of the emm55 gene by tumor cells leading to a broad immune response that may overcome the primary and secondary resistance against immune checkpoint inhibitors in patients with advanced skin cancer including Merkel cell carcinoma (NCT04853602) 74 …”

“…In patients with localized or locally advanced Merkel cell carcinoma, administration of T-VEC prior to surgery and/or radiotherapy is investigated as monotherapy or in combination with immune checkpoint inhibitors to determine response rates and immunological changes in the microenvironment of the tumor (NCT02819843, NCT02978625, NCT03458117). 74 In addition, therapeutic vaccines targeting tumorassociated antigens or viral oncoproteins are also being developed, as they may be interesting in the perioperative phase of skin cancers like Merkel cell carcinoma to reduce the tumor volume, eliminate potential micrometastases, and, ultimately, to prevent recurrence. 74 Clinical trials are currently underway to investigate vaccines in metastatic or locally advanced Merkel cell carcinoma (NCT04160065, NCT04246671).…”

“…74 In addition, therapeutic vaccines targeting tumorassociated antigens or viral oncoproteins are also being developed, as they may be interesting in the perioperative phase of skin cancers like Merkel cell carcinoma to reduce the tumor volume, eliminate potential micrometastases, and, ultimately, to prevent recurrence. 74 Clinical trials are currently underway to investigate vaccines in metastatic or locally advanced Merkel cell carcinoma (NCT04160065, NCT04246671). Interestingly, IFx-Hu2.0 is an experimental intralesional vaccine inducing the expression of the emm55 gene by tumor cells leading to a broad immune response that may overcome the primary and secondary resistance against immune checkpoint inhibitors in patients with advanced skin cancer including Merkel cell carcinoma (NCT04853602).…”

Kutane Metastasen: Von der Epidemiologie bis zur Therapie

“…64 Andere Therapiekombinationen werden ebenfalls derzeit in klinischen Studien untersucht. 73 74 Therapeutische Impfstoffe, die auf tumorassoziierte Antigene oder virale Onkoproteine abzielen, werden ebenfalls entwickelt, da sie in der perioperativen Phase von Hautkrebserkrankungen wie dem Merkelzellkarzinom besonders interessant sein könnten, um das Tumorvolumen zu verringern, potenzielle Mikrometastasen zu beseitigen und schließlich ein erneutes Auftreten zu verhindern. 74 Derzeit laufen klinische Studien zur Untersuchung von Impfstoffen bei metastasiertem oder lokal fortgeschrittenem Merkelzellkarzinom (NCT04160065, NCT04246671).…”

“…73 74 Therapeutische Impfstoffe, die auf tumorassoziierte Antigene oder virale Onkoproteine abzielen, werden ebenfalls entwickelt, da sie in der perioperativen Phase von Hautkrebserkrankungen wie dem Merkelzellkarzinom besonders interessant sein könnten, um das Tumorvolumen zu verringern, potenzielle Mikrometastasen zu beseitigen und schließlich ein erneutes Auftreten zu verhindern. 74 Derzeit laufen klinische Studien zur Untersuchung von Impfstoffen bei metastasiertem oder lokal fortgeschrittenem Merkelzellkarzinom (NCT04160065, NCT04246671). Interessanterweise ist IFx-Hu2.0 ein experimenteller intraläsionaler Impfstoff, der die Expression des emm55-Gens durch Tumorzellen induziert und zu einer breiten Immunantwort führen kann, die möglicherweise die primäre und sekundäre Resistenz gegen Immuncheckpoint-Inhibitoren bei Patienten mit fortgeschrittenem Hautkrebs, einschließlich Merkelzellkarzinom, überwinden kann (NCT04853602).…”