Targeting Merkel cell carcinoma by engineered T cells specific to T-antigens of Merkel cell polyomavirus

Purpose: The causative agent of most cases of Merkel cell carcinoma (MCC) has been identified as the Merkel cell polyomavirus (MCV). MCV-encoded T-antigens (Tags) are essential not only for virus-mediated tumorigenesis but also for maintaining MCC cell lines in vitro. MCV Tags are thus an appealing target for viral oncoprotein-directed T cell therapy for MCC. With this study, we aimed to isolate and characterize Tag-specific T cell receptors (TCR) for potential use in gene therapy clinical trials. Experimental Design: T cell responses against MCV Tag epitopes were investigated by immunizing transgenic mice that express a diverse human TCR repertoire restricted to HLA-A2. Human lymphocytes genetically engineered to express Tag-specific TCRs were tested for specific reactivity against MCC cell lines. The therapeutic potential of Tag-specific TCR gene therapy was tested in a syngeneic cancer model. Results: We identified naturally processed epitopes of MCV Tags and isolated Tag-specific TCRs. T cells expressing these TCRs were activated by HLA-A2-positive cells loaded with cognate peptide or cells that stably expressed MCV Tags. We showed cytotoxic potential of T cells engineered to express these TCRs in vitro and demonstrated regression of established tumors in a mouse model upon TCR gene therapy. Conclusions: Our findings demonstrate that MCC cells can be targeted by MCV Tag-specific TCRs. Although recent findings suggest that approximately half of MCC patients benefit from PD1 pathway blockade, additional patients may benefit if their endogenous T cell response can be augmented by infusion of transgenic MCV-specific T cells such as those described here.

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