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

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

Author information

1
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
2
Institute of Immunology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
3
Berlin Institute of Health, Berlin, Germany.
4
German Cancer Research Center, Heidelberg, Germany.
5
University of Washington, Dermatology/Medicine/Pathology, Seattle, Washington.
6
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. tblanke@mdc-berlin.de.

Abstract

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.

PMID:
29669806
PMCID:
PMC6082703
[Available on 2019-08-01]
DOI:
10.1158/1078-0432.CCR-17-2661

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