Merkel polyomavirus specific transgenic T cell receptor therapy in PD-1 inhibitor refractory Merkel cell carcinoma

9549 Background: Merkel cell carcinoma is an aggressive neuroendocrine tumor of skin origin with most cases caused by the Merkel polyoma virus (MCPyV). While many patients benefit from PD-1/PD-L1 axis blockade, most patients do not respond or develop resistance. We sought to ask whether adoptive transfer of autologous T cells transduced with MCPyV specific T cells could lead to clinical responses in PD-1 inhibitor refractory patients. Methods: Five MCPyV positive, HLA-A02 patients with PD-1 inhibitor refractory metastatic Merkel cell carcinoma were treated with adoptive transfer of CD62L+ CD8+ and CD4+ autologous T cells transduced with a T cell receptor (TCR) targeting an HLA-A0201 restricted MCPyV epitope. Two different strategies were used to facilitate T cell expansion: In 3 patients, single fraction radiation was administered to a subset of lesions prior to T cell transfer. In 2 patients, lymphodepleting chemotherapy with cyclophosphamide and fludarabine was administered prior to T cell transfer. Anti PD-1/PD-L1 therapy was given 14 days after T cell infusion. Transgenic T cells were visualized in tumor biopsies by multiplex immunohistochemistry. Results: 5 patients were treated, with 4 patients receiving 100 million tetramer positive CD8+ T cells and one patient receiving 500 million cells. 3 patients received second infusions with between 300 million and 900 million tetramer positive cells. No dose limiting toxicities or cytokine release syndrome were observed. T cell persistence was lower in the 2 patients treated with lymphodepleting chemotherapy relative to the 3 patients treated with single fraction radiation. Transgenic T cells persisted at tumor sites greater than 1 month following transfer. 4 patients experienced progressive disease, and a single patient had a mixed response and greater than 1 year disease free interval following local therapy of an isolated site of progression. The responding patient was the only patient with class I MHC staining on tumor cells prior to treatment, and the site of local progression in that patient showed the presence of TCR transgenic T cells but loss of class I MHC expression. Conclusions: MCPyV specific transgenic T cells are safe, traffic to tumor sites, and can result in a clinical response, but their clinical activity may be limited by down-regulation of class I MHC expression on tumors. A future trial will address strategies to increase class I MHC expression on Merkel tumors. Clinical trial information: NCT03747484.