Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia
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Fabio Forghieri1,*, Giovanni Riva2,*, Ivana Lagreca1,*, Patrizia Barozzi1, Daniela Vallerini1, Monica Morselli1, Ambra Paolini1, Paola Bresciani1, Elisabetta Colaci1, Monica Maccaferri1, Andrea Gilioli1, Vincenzo Nasillo1, Andrea Messerotti1, Valeria Pioli1, Laura Arletti1, Davide Giusti1, Francesca Bettelli1, Melania Celli1, Francesca Donatelli1, Giorgia Corradini1, Sabrina Basso3,4, Antonella Gurrado3,4, Monica Cellini5, Tommaso Trenti2, Roberto Marasca1, Franco Narni1, Maria Paola Martelli6, Brunangelo Falini6, Leonardo Potenza1,*, Mario Luppi1,* and Patrizia Comoli3,4,*
1Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero Universitaria Policlinico, Modena, Italy
2Department of Laboratory Medicine and Pathology, Unità Sanitaria Locale, Modena, Italy
3Pediatric Hematology/Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
4Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
5Department of Medical and Surgical Sciences, Section of Pediatric Hemato-Oncology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Policlinico, Modena, Italy
6Institute of Hematology, Centro di Ricerca Emato-Oncologico, University of Perugia, Ospedale S. Maria della Misericordia, S. Andrea delle Fratte, Perugia, Italy
*These authors equally contributed to this work
Patrizia Comoli, email: firstname.lastname@example.org
Keywords: acute myeloid leukemia; immunity; NPM1 mutation; T cell therapy
Received: October 17, 2018 Accepted: January 03, 2019 Published: January 25, 2019
Nucleophosmin(NPM1)-mutated protein, a leukemia-specific antigen, represents an ideal target for AML immunotherapy. We investigated the dynamics of NPM1-mutated-specific T cells on PB and BM samples, collected from 31 adult NPM1-mutated AML patients throughout the disease course, and stimulated with mixtures of 18 short and long peptides (9-18mers), deriving from the complete C-terminal of the NPM1-mutated protein. Two 9-mer peptides, namely LAVEEVSLR and AVEEVSLRK (13.9–14.9), were identified as the most immunogenic epitopes. IFNγ-producing NPM1-mutated-specific T cells were observed by ELISPOT assay after stimulation with peptides 13.9–14.9 in 43/85 (50.6%) PB and 34/80 (42.5%) BM samples. An inverse correlation between MRD kinetics and anti-leukemic specific T cells was observed. Cytokine Secretion Assays allowed to predominantly and respectively identify Effector Memory and Central Memory T cells among IFNγ–producing and IL2–producing T cells. Moreover, NPM1-mutated-specific CTLs against primary leukemic blasts or PHA-blasts pulsed with different peptide pools could be expanded ex vivo from NPM1-mutated AML patients or primed in healthy donors. We describe the spontaneous appearance and persistence of NPM1-mutated-specific T cells, which may contribute to the maintenance of long-lasting remissions. Future studies are warranted to investigate the potential role of both autologous and allogeneic adoptive immunotherapy in NPM1-mutated AML patients.
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