Effective control of acute myeloid leukaemia and acute lymphoblastic leukaemia progression by telomerase specific adoptive T-cell therapy

Abstract

// Sara Sandri 1,* , Francesco De Sanctis 1,* , Alessia Lamolinara 2 , Federico Boschi 3 , Ornella Poffe 1 , Rosalinda Trovato 1 , Alessandra Fiore 1 , Sara Sartori 1 , Andrea Sbarbati 4 , Attilio Bondanza 5 , Simone Cesaro 6 , Mauro Krampera 7 , Maria T. Scupoli 7,8 , Michael I. Nishimura 9 , Manuela Iezzi 2 , Silvia Sartoris 1 , Vincenzo Bronte 1 and Stefano Ugel 1 1 Department of Medicine, University of Verona, Section of Immunology, Verona, Italy 2 Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), G. D’Annunzio University, Chieti-Pescara, Italy 3 Department of Computer Science, University of Verona, Verona, Italy 4 Department of Neurological and Movement Sciences, University of Verona, Verona, Italy 5 Innovative Immunotherapies Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Hospital Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy 6 Department of Pediatric Haematology Oncology, University of Verona, Verona, Italy 7 Department of Medicine, University of Verona, Section of Haematology, Verona, Italy 8 University of Verona, Interdepartmental Laboratory for Medical Research (LURM), Verona, Italy 9 Department of Surgery, Loyola University Medical Center, Maywood, IL, United States * These authors have contributed equally to this work Correspondence to: Stefano Ugel, email: // Keywords : acute myeloid leukaemia (AML), B-cell acute lymphoblastic leukaemia (B-ALL), telomerase (TERT), TCR-redirected T-cells, adoptive cell therapy (ACT) Received : November 08, 2016 Accepted : May 12, 2017 Published : May 23, 2017 Abstract Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice. In the present report, we show the ability of our approach to limit the progression of more aggressive leukemic pathologies, such as acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL). Together, our findings demonstrate that TERT-based adoptive cell therapy is a concrete platform of T cell-mediated immunotherapy for leukaemia treatment.