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| Item Type: | Article |
|---|---|
| Title: | Targeting Merkel cell carcinoma by engineered T cells specific to T-antigens of Merkel cell polyomavirus |
| Creators Name: | Gavvovidis, I., Leisegang, M., Willimsky, G., Miller, N.J., Nghiem, P. and Blankenstein, T. |
| 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 (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. Experimantal 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. |
| Keywords: | Carcinogenesis, Epitopes, Genetic Therapy, HLA-A2 Antigen, Immunologic Cytotoxicity, Immunotherapy, Lymphocytes, Merkel Cell Carcinoma, Merkel Cell Polyomavirus, Neoplastic Gene Expression Regulation, Programmed Cell Death 1 Receptor, T-Cell Antigen Receptors, T-Lymphocytes, Transgenic Mice, Tumor Viral Antigens, Viral Oncogene Proteins, Animals, Mice |
| Source: | Clinical Cancer Research |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Volume: | 24 |
| Number: | 15 |
| Page Range: | 3644-3655 |
| Date: | August 2018 |
| Official Publication: | https://doi.org/10.1158/1078-0432.CCR-17-2661 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
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