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.
Highlights
The development of adoptive cell therapy (ACT) represents an emerging and realistic approach to treat cancer patients
A, B cells immunomagnetically isolated from splenocytes of positive or negative transgenic and with only normal (WT) mice were tested for TERT expression by Western blot and TERT activity by TRAP assay
We show here the strength and safety of a broadly applicable immunotherapy protocol based on engineered T cells generated by transduction with a high-affinity T-cell receptor (TCR) capable of recognizing the complex formed by hTERT865–873 peptide and HLA-A2 molecule
Summary
The development of adoptive cell therapy (ACT) represents an emerging and realistic approach to treat cancer patients. The clinical response following adoptive TIL transfer was associated with T cells reactive toward mutated epitopes that were able to persist in patients for at least 1 month after lymphocyte infusion [6]. These boundaries intrinsic to TILbased ACT could be surmounted by gene therapy strategies based on genetically engineered lymphocytes where the desired TCR sequence insertion, by a virus-mediated delivery into na€ve T cells, can confer an antigen-oriented immune specificity [7,8,9]. TCR can be isolated from mouse CTLs primed in vivo by vaccination of transgenic mice bearing human HLA-A2 molecules [14, 15], an
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