Generation of donor-derived Wilms tumor antigen 1–specific cytotoxic T lymphocytes with potent anti-leukemia activity for somatic cell therapy in children given haploidentical stem cell transplantation: a feasibility pre-clinical study

• Published in: Cytotherapy (Oxford, England) England), 2019-09, Vol.21 (9), p.958-972
• Main Authors: Ferulli, Federica, Tanzi, Matteo, Turin, Ilaria, Montini, Enrica, Rosti, Vittorio, Acquafredda, Gloria, Lisini, Daniela, Compagno, Francesca, Boghen, Stella, Licari, Amelia, Marseglia, Gianluigi, Zecca, Marco, Montagna, Daniela
• Format: Article
• Language: English
• Subjects: acute leukemia; Advanced Basic Science; allogeneic hematopoietic stem cell transplantation; anti-tumor immunotherapy; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; cytotoxic T lymphocytes; Cytotoxicity, Immunologic; Dendritic Cells - immunology; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - immunology; Humans; Interferon-gamma - biosynthesis; Leukemia - immunology; Leukemia - therapy; Male; Other; Peptides - metabolism; Phenotype; somatic cell therapy; T-Lymphocytes, Cytotoxic - immunology; Tissue Donors; Transplantation, Haploidentical; Wilms tumor antigen 1; WT1 Proteins - immunology
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2019.06.007

AbstractBackgroundThe Wilms tumor antigen 1 (WT1) is over-expressed in a vast majority of adult and childhood acute leukemia and myelodysplastic syndromes, being lowly or transiently expressed in normal tissues and hematopoietic stem cells (HSCs). A number of HLA-restricted WT1 epitopes are immunogenic, allowing the in vitro induction of WT1-specific cytotoxic T lymphocytes (CTLs) from patients and healthy donors. AimThe aim of the study was to investigate the feasibility of producing WT1-specific CTLs suitable for somatic cell therapy to prevent or treat relapse in children with acute myeloid or lymphoblastic leukemia given haploidentical HSC transplantation (haplo-HSCT). MethodsFor WT1-specific CTL production, donor-derived either peripheral blood mononuclear cells (PBMCs) or CD8+ lymphocytes were stimulated with WT1 peptide-loaded donor dendritic cells in the presence of interleukin (IL)-7 and IL-12. Effector cells were re-stimulated once with irradiated donor PBMCs pulsed with WT1-peptides, and then expanded in an antigen-independent way. ResultsWT1-specific CTLs, displaying high-level cytotoxicity against patients’ leukemia blasts and negligible activity against patients’ non-malignant cells, were obtained from both PBMCs and CD8+ lymphocytes. WT1-specific CTLs obtained from PBMCs showed a better expansion capacity and better anti-leukemia activity than those obtained from CD8+ lymphocytes, even though the difference was not statistically significant. In CTLs derived from PBMCs, both CD8+ and CD4+ subpopulations displayed strong anti-leukemia cytotoxic activity. DiscussionResults of this pre-clinical study pave the way to a somatic cell therapy approach aimed at preventing or treating relapse in children given haplo-HSCT for WT1-positive leukemia.