Polyomavirus‐driven Merkel cell carcinoma: Prospects for therapeutic vaccine development

Abstract

Great strides have been made in cancer immunotherapy including the breakthrough successes of anti-PD-(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD-(L)1 blockade is highly effective. Yet,~50% of patients either do not respond to therapy or develop PD-(L)1 refractory disease and, thus, do not experience long-term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor-associated antigens, mutated self-antigens, or immunogenic viral oncoproteins are currently being developed to augment T-cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T-antigen (T-Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T-Ag elicits specific B-and T-cell immune responses in most persons with virus-positive MCC (VP-MCC), and ongoing T-Ag expression is required to drive VP-MCC cell proliferation, therapeutic vaccination with T-Ag is a rational potential component of immunotherapy. Failure of the endogenous T-cell response to clear VP-MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T-cell activity against tumor cells. Here, we review the relevant underlying biology of VP-MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP-MCC patients could potentially benefit from a therapeutic vaccine. K E Y W O R D S cancer therapeutic vaccine, immunotherapy, MCPyV, Merkel cell carcinoma

Merkel Cell Polyomavirus and Merkel Cell Carcinoma

“…Another option is preventive vaccination with T antigens. Approximately 1% of non-MCC patients have low titer of antibodies against these oncoprotein probably because of low viral activity or latent infection and the fact that LT is a nuclear protein, reducing its processing and presentation by HLA class 1 [ 251 ]. However, seroprevalence and titers increase significantly in MCC patients [ 221 ].…”

“…Therapeutic vaccination to improve the immune system of MCC patient offers another alternative. For an excellent recent review, the reader is referred to [ 251 ]. Therapeutic vaccination with MCPyV T antigens can support improperly primed T cells and stimulate naive CD T cells.…”

A case of complete spontaneous regression of extensive Merkel cell carcinoma involving the orbit

“…2,3,5 Rare mutational events and immune senescence may enable MCPyV clonal integration into the host genome, contributing to MCC oncogenesis. 6 MCPyV-negative MCC may be attributed to UV mutations related to prolonged UV exposure. 6 The presence of MCPyV within tumour cells may provide an immunestimulatory signal that generates a systemic response targeting MCPyV-positive tumour cells.…”

Harnessing the power of the immune system in cancer immunotherapy and cancer prevention

“…Tabachnick‐Cherny S et al review an alternative approach, that is, the development of a therapeutic vaccine based on the T‐Ag. The authors discuss the underlying biology, antigen delivery formats, and potential benefits for this therapeutic vaccine as well as in combination with anti‐PD‐L1 therapy 18 …”