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.
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