1. 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
- Author
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Daniela Lisini, Vittorio Rosti, Francesca Compagno, Matteo Tanzi, Gian Luigi Marseglia, Marco Zecca, Enrica Montini, Federica Ferulli, Gloria Acquafredda, Ilaria Turin, Amelia Licari, Daniela Montagna, and Stella Boghen
- Subjects
0301 basic medicine ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,Myeloid ,Immunology ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,Interferon-gamma ,0302 clinical medicine ,Antigen ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,WT1 Proteins ,Genetics (clinical) ,Cell Proliferation ,Transplantation ,Acute leukemia ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,hemic and immune systems ,Cell Biology ,Dendritic Cells ,medicine.disease ,Hematopoietic Stem Cells ,Tissue Donors ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Oncology ,030220 oncology & carcinogenesis ,Transplantation, Haploidentical ,Cancer research ,Feasibility Studies ,Female ,Stem cell ,business ,Peptides ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Background The 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. Aim The 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). Methods For 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. Results WT1-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. Discussion Results 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.
- Published
- 2019