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

Gavvovidis, Ioannis ; Leisegang, Matthias ; Willimsky, Gerald ; Miller, Natalie ; Nghiem, Paul ; Blankenstein, Thomas

Clinical cancer research, 2018-08, Vol.24 (15), p.3644-3655 [Periódico revisado por pares]

United States: American Association for Cancer Research Inc

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Título:
Targeting Merkel Cell Carcinoma by Engineered T Cells Specific to T-Antigens of Merkel Cell Polyomavirus
Autor: Gavvovidis, Ioannis ; Leisegang, Matthias ; Willimsky, Gerald ; Miller, Natalie ; Nghiem, Paul ; Blankenstein, Thomas
Assuntos: Animals ; Antigens ; Antigens, Viral, Tumor - genetics ; Antigens, Viral, Tumor - immunology ; Antigens, Viral, Tumor - therapeutic use ; Biotechnology ; Cancer ; Carcinogenesis - genetics ; Carcinogenesis - immunology ; Carcinoma, Merkel Cell - genetics ; Carcinoma, Merkel Cell - immunology ; Carcinoma, Merkel Cell - therapy ; Carcinoma, Merkel Cell - virology ; Clinical trials ; Cytotoxicity ; Cytotoxicity, Immunologic - genetics ; Design of experiments ; Epitopes ; Epitopes - immunology ; Experimental design ; Gene Expression Regulation, Neoplastic - immunology ; Gene therapy ; Genetic engineering ; Genetic Therapy ; Histocompatibility antigen HLA ; HLA-A2 Antigen - genetics ; HLA-A2 Antigen - immunology ; HLA-A2 Antigen - therapeutic use ; Humans ; Immunization ; Immunotherapy ; Lymphocytes ; Lymphocytes - immunology ; Lymphocytes T ; Medical research ; Merkel cell polyomavirus - immunology ; Merkel cell polyomavirus - pathogenicity ; Mice ; Mice, Transgenic ; Oncogene Proteins, Viral - immunology ; Oncogene Proteins, Viral - therapeutic use ; Patients ; PD-1 protein ; Programmed Cell Death 1 Receptor - antagonists & inhibitors ; Programmed Cell Death 1 Receptor - immunology ; Receptors ; Receptors, Antigen, T-Cell - genetics ; Receptors, Antigen, T-Cell - immunology ; Receptors, Antigen, T-Cell - therapeutic use ; T cell receptors ; T-cell receptor ; T-Lymphocytes - immunology ; Tags ; Transgenic mice ; Tumorigenesis ; Viruses
É parte de: Clinical cancer research, 2018-08, Vol.24 (15), p.3644-3655
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SourceType-Scholarly Journals-1
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Descrição: 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 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. 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. 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 and demonstrated regression of established tumors in a mouse model upon TCR gene therapy. 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. .
Editor: United States: American Association for Cancer Research Inc
Idioma: Inglês

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

Gavvovidis, Ioannis ; Leisegang, Matthias ; Willimsky, Gerald ; Miller, Natalie ; Nghiem, Paul ; Blankenstein, Thomas

United States: American Association for Cancer Research Inc

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