Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies Journal Article

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Authors: Sandri, S.; Bobisse, S.; Moxley, K.; Lamolinara, A.; De Sanctis, F.; Boschi, F.; Sbarbati, A.; Fracasso, G.; Ferrarini, G.; Hendriks, R. W.; Cavallini, C.; Scupoli, M. T.; Sartoris, S.; Iezzi, M.; Nishimura, M. I.; Bronte, V.; Ugel, S.
Article 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. (c)2016 AACR.
Journal Title: Cancer research
Volume: 76
Issue: 9
ISSN: 1538-7445; 0008-5472
Publisher: American Association for Cancer Research  
Journal Place: United States
Date Published: 2016
Start Page: 2540
End Page: 2551
Language: eng
DOI/URL:

10.1158/0008-5472.CAN-15-2318
Notes: CI: (c)2016; JID: 2984705R; 2015/08/24 [received]; 2016/01/24 [accepted]; ppublish