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NK Cell-Based Immunotherapy for Hematological Malignancies
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NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells

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Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, 00161 Rome, Italy
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Department of Pediatric Hematology/Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Pediatrico Bambino Gesù, 00165 Rome, Italy
3
Department of Pediatrics, Sapienza, University of Rome, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2019, 8(11), 1904; https://doi.org/10.3390/jcm8111904
Received: 19 September 2019 / Revised: 29 October 2019 / Accepted: 5 November 2019 / Published: 7 November 2019
T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56lowCD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56lowCD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56lowCD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56lowCD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients. View Full-Text
Keywords: NK cell subsets; Bone marrow transplantation; haematological disease; iCasp-9 HSCT NK cell subsets; Bone marrow transplantation; haematological disease; iCasp-9 HSCT
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Stabile, H.; Nisti, P.; Fionda, C.; Pagliara, D.; Gaspari, S.; Locatelli, F.; Santoni, A.; Gismondi, A. NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells. J. Clin. Med. 2019, 8, 1904.

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