Reprogramming engineered autologous T cells to overcome resistance in Merkel cell carcinoma [scRNA-seq]

Immune checkpoint inhibitors (CPIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified TCRMCC1, a highly-avid, HLA-A*02:01-restricted T cell receptor (TCR) targeting the Merkel Cell Polyoma Virus (MCPyV) oncoprotein LTAg15–23. Seven patients with CPI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1) following lymphodepleting chemotherapy or HLA-enhancing interventions (radiation or IFNg-1b [Actimmune®]), with concurrent CPIs (NCT03747484). TTCR-MCC1 trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 to co-express CD8ab and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell co-stimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow 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.