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. Clin Cancer Res; 24(9); 2035-43. ©2017 AACR.

Figure 1. Clinical and histologic appearance of MCC

Left: Clinical appearance of an MCC arising on the left cheek of a 55 year old man. The tumor was red, firm, non-tender, and rapidly growing on sun-exposed skin. The differential diagnosis would include other types of non-melanoma skin cancer. Center: Intradermal tumor with pleiomorphic cells with large nuclei and scant cytoplasm. Right: Cytokeratin-20 (CK-20) immunohistochemical staining exhibits the characteristic peri-nuclear expression of CK-20, a highly diagnostic finding for MCC.

Figure 2. Comparison of virus-positive and virus-negative MCC tumors

This schematic depicts the two major causes of MCC, their prevalence, differences in their potential immune targets, and frequencies of response to immune therapy. Top: Differences in MCC prevalence – US/Europe vs. Australia. Left: Virus-induced tumorigenesis – The highly prevalent Merkel cell polyomavirus (MCPyV) is often found on normal skin. Rarely, MCPyV will integrate into the host genome and through a separate rare event, large T will become truncated (tLT; depicted by red X's) prior its C-terminal. Expresssion of the sT and tLT viral oncogenes is tumorigenic through multiple pathways including inhibition of wild-type cellular Rb (see text). Right: UV-induced tumorigenesis – Sun exposure results in the generation of many UV-signature mutations (C->T mutations). The most common of which are in Rb and p53. Rb is frequently found to be inactivated in MCC tumors (67%). Mutation of p53 includes both activating and inactivating mutations. References (16, 18-21, 40-43, 71-75)