Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR) MCC1, a highly avid, HLA-A*02:01–restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen 15–23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCR MCC1-transduced cells (T TCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 T TCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLA low MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.
