title: Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies.
abstract: Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2-restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self-MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540-51. ©2016 AACR.
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sandri
authors.affiliation: Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, California.
authors.forename: Kelly
authors.initials: K
authors.lastname: Moxley
authors.affiliation: CESI Aging Research Center, G. D'Annunzio University, Chieti Scalo, Chieti, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lamolinara
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Sanctis
authors.affiliation: Department of Computer Science, University of Verona, Verona, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Boschi
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sbarbati
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ferrarini
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: University of Verona, Interdepartmental Laboratory for Medical Research (LURM), Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavallini
authors.affiliation: University of Verona, Interdepartmental Laboratory for Medical Research (LURM), Verona, Italy. Department of Medicine, Section of Hematology, University of Verona, Verona, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Scupoli
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sartoris
authors.affiliation: CESI Aging Research Center, G. D'Annunzio University, Chieti Scalo, Chieti, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, California.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Nishimura
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy. vincenzo.bronte@univr.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Medicine, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ugel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005240:Feasibility Studies; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D019098:Telomerase / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; C509186:TERT protein, human; D019098:Telomerase