Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus

Clin Cancer Res. 2018 Aug 1;24(15):3644-3655. doi: 10.1158/1078-0432.CCR-17-2661. Epub 2018 Apr 18.


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 (Tag) 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 PD-1 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. Clin Cancer Res; 24(15); 3644-55. ©2018 AACR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Viral, Tumor / genetics
  • Antigens, Viral, Tumor / immunology
  • Antigens, Viral, Tumor / therapeutic use*
  • Carcinogenesis / genetics
  • Carcinogenesis / immunology
  • Carcinoma, Merkel Cell / genetics
  • Carcinoma, Merkel Cell / immunology
  • Carcinoma, Merkel Cell / therapy*
  • Carcinoma, Merkel Cell / virology
  • Cytotoxicity, Immunologic / genetics
  • Epitopes / immunology
  • Gene Expression Regulation, Neoplastic / immunology
  • Genetic Therapy*
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology
  • HLA-A2 Antigen / therapeutic use
  • Humans
  • Immunotherapy
  • Lymphocytes / immunology
  • Merkel cell polyomavirus / immunology
  • Merkel cell polyomavirus / pathogenicity
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Viral / immunology
  • Oncogene Proteins, Viral / therapeutic use
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / therapeutic use
  • T-Lymphocytes / immunology*


  • Antigens, Viral, Tumor
  • Epitopes
  • HLA-A2 Antigen
  • Oncogene Proteins, Viral
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell