Background: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer, with an incidence that has doubled in the last 20 years to approximately 3000 cases/year in the US. Over one-third of patients will develop widespread disease, and survival in these patients has been historically poor with a 5-year survival rate of < 10%. MCC is highly immune-sensitive due to the antigenicity of the cancer-causing Merkel cell polyomavirus (MCPyV) expressed in most MCC tumors. Although immune checkpoint inhibitors (ICIs) targeting the PD-(L)1 axis show promising efficacy, most MCC patients will eventually relapse. There is no standard of care for patients that become refractory to ICIs. We hypothesize that cellular immune therapies targeting MCPyV may provide additional clinical benefit to these patients. To test this, we have engineered high-affinity TCR T cells against MCPyV and initiated a clinical trial. Methods: NCT03747484 is an ongoing phase I/II, open label, investigator-initiated trial (IIT) of FH-MCVA2TCR in combination with an anti-PD-(L)1 checkpoint inhibitor and an agent to upregulate MHC-I expression on tumor cells. The trial is conducted in patients aged 18 years or older with metastatic or unresectable, histologically confirmed virus-positive MCC whose disease has progressed on or after treatment with a PD-(L)1 axis checkpoint inhibitor. Patients undergo leukapheresis to collect white blood cells (WBCs) for TCR T cell product manufacturing. The cell product is administered on day 0. Patients receive an agent to upregulate MHC-I on tumor cells and continue on an anti-PD-(L)1 checkpoint inhibitor for up to one year. In phase I, three patients receive up to two infusions of dose level 1 of the T cell product. The primary objectives of phase I are to determine safety and tolerability based on dose-limiting toxicities (DLT) during an observation period of 28 days after the first infusion. Phase II enrolls patients at dose level 2. The total sample size of phase II is 12 patients. The first three patients are enrolled in a staggered manner and observed for DLTs. If no DLTs occur, the remaining sample size is accrued in open enrollment. The main objectives of phase II are safety based on number of adverse events and preliminary efficacy based on tumor response according to RECISTv1.1 and iRECIST. Secondary/exploratory objectives include cellular kinetics of TCR T cells, T cell phenotype, tumor infiltration kinetics, and MHC-I expression dynamics over time. After the first 12 months, patients transition to a long-term follow-up (LTFU) study for up to 15 years as per FDA guidelines. Clinical trial information: NCT03747484.