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1.
Haematologica ; 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38813718

RESUMEN

Mucosal-associated invariant T (MAIT) cells are innate-like T-cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematological malignancies undergoing allo-HSCT, between April/2019 and May/2022, from unrelated matched donor (MUD, n=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, n=93) donor after in vitro αßT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (12-49), overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM) were 79.5%, 72% and 7%, respectively; GvHD-free, Relapse-free Survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While WWT-cells reconstituted 1-2 years post-HSCT, MAIT-cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS and NRM were not affected by MAIT-cells. Interestingly, higher MAIT-cells at day+30 correlated with higher incidence of grade II-IV acute GvHD (19% vs 7%, p=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (17% vs 6%, p=0.07) resulting in lower GRFS (55% vs 73%, p=0.05). Higher MAIT-cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs 24%, p=0.02 and 9% vs 18%, p=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation and late BSI.

2.
Blood ; 143(3): 279-289, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-37738655

RESUMEN

ABSTRACT: TCRαß/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Niño , Humanos , Receptores de Antígenos de Linfocitos T alfa-beta , Trasplante Haploidéntico/efectos adversos , Antígenos HLA , Trasplante de Células Madre Hematopoyéticas/métodos , Antígenos de Histocompatibilidad Clase II , Recurrencia , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos
3.
Blood ; 142(2): 146-157, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37172203

RESUMEN

Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell-associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO-CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO-CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto Joven , Humanos , Niño , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfocitos T , Enfermedad Injerto contra Huésped/etiología , Inmunoterapia Adoptiva/efectos adversos , Antígenos CD19
4.
N Engl J Med ; 388(14): 1284-1295, 2023 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-37018492

RESUMEN

BACKGROUND: Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma. METHODS: In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). RESULTS: A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×106 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×106 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively. CONCLUSIONS: The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).


Asunto(s)
Inmunoterapia Adoptiva , Neuroblastoma , Receptores Quiméricos de Antígenos , Niño , Humanos , Caspasa 9/efectos adversos , Caspasa 9/genética , Caspasa 9/metabolismo , Caspasa 9/uso terapéutico , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/terapia , Neuroblastoma/genética , Neuroblastoma/terapia , Receptores Quiméricos de Antígenos/uso terapéutico
6.
Blood Adv ; 6(1): 281-292, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-34592755

RESUMEN

Several nonmalignant disorders (NMDs), either inherited or acquired, can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Between January 2012 and April 2020, 70 consecutive children affected by primary immunodeficiencies, inherited/acquired bone marrow failure syndromes, red blood cell disorders, or metabolic diseases, lacking a fully matched donor or requiring urgent transplantation underwent TCRαß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative as part of a prospective study. The median age at transplant was 3.5 years (range 0.3-16.1); the median time from diagnosis to transplant was 10.5 months (2.7 for SCID patients). Primary engraftment was obtained in 51 patients, while 19 and 2 patients experienced either primary or secondary graft failure (GF), the overall incidence of this complication being 30.4%. Most GFs were observed in children with disease at risk for this complication (eg, aplastic anemia, thalassemia). All but 5 patients experiencing GF were successfully retransplanted. Six patients died of infectious complications (4 had active/recent infections at the time of HSCT), the cumulative incidence of transplant-related mortality (TRM) being 8.5%. Cumulative incidence of grade 1-2 acute GVHD was 14.4% (no patient developed grade 3-4 acute GVHD). Only one patient at risk developed mild chronic GVHD. With a median follow-up of 3.5 years, the 5-year probability of overall and disease-free survival was 91.4% and 86.8%, respectively. In conclusion, TCRαß/CD19-depleted haploidentical HSCT from an HLA-partially matched relative is confirmed to be an effective treatment of children with NMDs. Prompt donor availability, low incidence of GVHD, and TRM make this strategy an attractive option in NMDs patients. The study is registered at ClinicalTrial.gov as NCT01810120.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adolescente , Niño , Preescolar , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T alfa-beta , Acondicionamiento Pretrasplante , Resultado del Tratamiento
7.
Front Immunol ; 12: 657329, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33986748

RESUMEN

A recent approach of hematopoietic stem cell (HSC) transplantation from haploidentical donors "mobilized" with G-CSF is based on the selective depletion of αß T and B lymphocytes from the graft. Through this approach, the patient receives both HSC and mature donor-derived effector cells (including NK cells), which exert both anti-leukemia activity and protection against infections. We previously showed that donor HSC mobilization with G-CSF results in accumulation in the graft of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), capable of inhibiting in vitro the anti-leukemia activity of allogeneic NK cells. Here, we performed a detailed gene expression analysis on NK cells and PMN-MDSCs both derived from mobilized graft. Cytotoxicity assays and real time PCR arrays were performed in NK cells. Microarray technology followed by bioinformatics analysis was used for gene expression profiling in PMN-MDSCs. Results indicate that NK cells from the graft have a lower cytolytic activity as compared to those from non-mobilized samples. Further, mobilized PMN-MDSCs displayed a peculiar transcriptional profile distinguishing them from non-mobilized ones. Differential expression of pro-proliferative and immune-modulatory genes was detected in mobilized PMN-MDSCs. These data strengthen the concept that G-CSF-mobilized PMN-MDSCs present in the graft display unique molecular characteristics, in line with the strong inhibitory effect on donor NK cells.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Neutrófilos/metabolismo , Transcriptoma , Supervivencia Celular , Biología Computacional/métodos , Citotoxicidad Inmunológica , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Células Asesinas Naturales/inmunología , Leucemia/terapia , Células Supresoras de Origen Mieloide/inmunología , Neutrófilos/inmunología , Transcriptoma/efectos de los fármacos , Trasplante Haploidéntico
8.
Blood Adv ; 5(5): 1333-1339, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33656536

RESUMEN

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αß (TCRαß+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαß+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.


Asunto(s)
Anemia de Fanconi , Trasplante de Células Madre Hematopoyéticas , Niño , Anemia de Fanconi/terapia , Humanos , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T alfa-beta , Acondicionamiento Pretrasplante , Adulto Joven
10.
Ann Clin Transl Neurol ; 6(10): 2110-2113, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31529689

RESUMEN

Neuromyelitis optica is an immune-mediated disease characterized by a relapsing course, resulting in progressive disability. In children, given the long life expectancy, a disease-modifying treatment could be particularly desirable. Unfortunately, the currently available treatment strategies with this potential are scarce. Very limited data are available about the use of allogeneic hematopoietic stem cell transplantation (HSCT) for autoimmune neurological diseases. In this report, we present a pediatric case successfully treated with allogeneic HSCT from an HLA-haploidentical donor, after ex vivo TCR/CD19-depletion of the graft. To the best of our knowledge, this is the first case of a pediatric patient to benefit from such a treatment.


Asunto(s)
Antígenos CD19 , Trasplante de Células Madre Hematopoyéticas , Depleción Linfocítica , Neuromielitis Óptica/terapia , Receptores de Antígenos de Linfocitos T , Trasplante Haploidéntico , Niño , Femenino , Humanos
11.
Cell Rep ; 20(4): 846-853, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28746870

RESUMEN

Herein, we demonstrate that HCMV miR-UL112-5p targets ERAP1, thereby inhibiting the processing and presentation of the HCMV pp65495-503 peptide to specific CTLs. In addition, we show that the rs17481334 G variant, naturally occurring in the ERAP1 3' UTR, preserves ERAP1 from miR-UL112-5p-mediated degradation. Specifically, HCMV miR-UL112-5p binds the 3' UTR of ERAP1 A variant, but not the 3' UTR of ERAP1 G variant, and, accordingly, ERAP1 expression is reduced both at RNA and protein levels only in human fibroblasts homozygous for the A variant. Consistently, HCMV-infected GG fibroblasts were more efficient in trimming viral antigens and being lysed by HCMV-peptide-specific CTLs. Notably, a significantly decreased HCMV seropositivity was detected among GG individuals suffering from multiple sclerosis, a disease model in which HCMV is negatively associated with adult-onset disorder. Overall, our results identify a resistance mechanism to HCMV miR-UL112-5p-based immune evasion strategy with potential implications for individual susceptibility to infection and other diseases.


Asunto(s)
Aminopeptidasas/metabolismo , Citomegalovirus/genética , Variación Genética/genética , MicroARNs/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Regiones no Traducidas 3'/genética , Aminopeptidasas/genética , Linfocitos T CD8-positivos/metabolismo , Infecciones por Citomegalovirus/enzimología , Infecciones por Citomegalovirus/genética , Genotipo , Humanos , MicroARNs/genética , Antígenos de Histocompatibilidad Menor/genética , Esclerosis Múltiple/enzimología , Esclerosis Múltiple/genética , Unión Proteica , ARN Mensajero/genética , ARN Viral/genética , Linfocitos T Citotóxicos/metabolismo
12.
Blood ; 130(5): 677-685, 2017 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-28588018

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αß T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αß T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120.


Asunto(s)
Linfocitos B , Trasplante de Células Madre Hematopoyéticas , Leucemia , Depleción Linfocítica , Receptores de Antígenos de Linfocitos T alfa-beta , Linfocitos T , Enfermedad Aguda , Adolescente , Adulto , Aloinjertos , Suero Antilinfocítico/administración & dosificación , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Lactante , Leucemia/mortalidad , Leucemia/terapia , Masculino , Tasa de Supervivencia
13.
Front Immunol ; 8: 332, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28386262

RESUMEN

Hematopoietic stem cell transplantation is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αß T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αß T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αß T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing, and presentation were fully preserved. Therefore, we propose that separated αß T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification.

14.
Biol Blood Marrow Transplant ; 22(11): 2056-2064, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27519279

RESUMEN

HLA-haploidentical family donors represent a valuable option for children requiring allogeneic hematopoietic stem cell transplantation (HSCT). Because graft-versus-host diseases (GVHD) is a major complication of HLA-haploidentical HSCT because of alloreactive T cells in the graft, different methods have been used for ex vivo T cell depletion. Removal of donor αß T cells, the subset responsible for GVHD, and of B cells, responsible for post-transplantation lymphoproliferative disorders, have been recently developed for HLA-haploidentical HSCT. This manipulation preserves, in addition to CD34+ progenitors, natural killer, γδ T, and monocytes/dendritic cells, contributing to anti-leukemia activity and protection against infections. We analyzed depletion efficiency and cell yield in 200 procedures performed in the last 3 years at our center. Donors underwent CD34+ hematopoietic stem cell (HSC) peripheral blood mobilization with granulocyte colony-stimulating factor (G-CSF). Poor CD34+ cell mobilizers (48 of 189, 25%) received plerixafor in addition to G-CSF. Aphereses containing a median of 52.5 × 109 nucleated cells and 494 × 106 CD34+ HSC were manipulated using the CliniMACS device. In comparison to the initial product, αß T cell depletion produced a median 4.1-log reduction (range, 3.1 to 5.5) and B cell depletion led to a median 3.4-log reduction (range, 2.0 to 4.7). Graft products contained a median of 18.5 × 106 CD34+ HSC/kg recipient body weight, with median values of residual αß T cells and B cells of 29 × 103/kg and 33 × 103/kg, respectively. Depletion efficiency monitored at 6-month intervals demonstrated steady performance, while improved recovery of CD34+ cells was observed after the first year (P = .0005). These data indicate that αß T cell and B cell depletion of HSC grafts from HLA-haploidentical donors was efficient and reproducible.


Asunto(s)
Antígenos HLA/inmunología , Depleción Linfocítica/métodos , Receptores de Antígenos de Linfocitos T alfa-beta , Trasplante Haploidéntico/métodos , Antígenos CD34/análisis , Linfocitos B/inmunología , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Linfocitos T/inmunología
15.
Transfus Apher Sci ; 54(3): 356-63, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27209628

RESUMEN

Hematopoietic Stem Cells Transplantation (HSCT) is an effective treatment for hematological and non-hematological diseases. The main challenge in autologous HSCT is purging of malignant cells to prevent relapse. In allogeneic HSCT graft-versus-host disease (GvHD) and opportunistic infections are frequent complications. Two types of graft manipulation have been introduced: the first one in the autologous context aimed at separating malignant cells from hematopoietic stem cells (HSC), and the second one in allogeneic HSCT aimed at reducing the incidence of GvHD and at accelerating immune reconstitution. Here we describe the manipulations used for cell purging in autologous HSCT or for T Cell Depletion (TCD) and T cell selection in allogeneic HSCT. More complex manipulations, requiring a Good Manufacturing Practice (GMP) facility, are briefly mentioned.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Depleción Linfocítica/métodos , Aloinjertos , Autoinjertos , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Humanos
16.
Blood Rev ; 30(4): 297-307, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27066851

RESUMEN

Hemopoietic stem cell transplantation (HSCT) is a standard procedure for treatment of malignant and non-malignant hematological diseases. HSCT donors include HLA-identical siblings, matched or mismatched unrelated donors and haploidentical related donors. Graft-versus-host disease (GvHD), mediated by donor alloreactive T-cells in the graft, can be triggered by minor histocompatibility antigens in HLA-identical pairs, by alleles at loci not considered for MUD-matching or by the mismatched haplotype in haplo-HSCT. Therefore, removal of donor T-cells, that contain the alloreactive precursors, is required, but T-cell depletion associates with opportunistic infections and with reduced graft-versus-leukemia effect. Selective T-cell depletion strategies have been introduced, like removal of αß T-lymphocytes and of naive T-cells, two subsets including the alloreactive precursors, but the ultimate goal is specific removal of alloreactive T-cells. Here we review the different approaches to deplete alloreactive T-cells only and discuss pros and cons, specificity, efficiency and efficacy. Combinations of different methods and innovative approaches are also proposed for depleting specific alloreactive T-cells with high efficiency.


Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Linfocitos T/inmunología , Acondicionamiento Pretrasplante/efectos adversos , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Acondicionamiento Pretrasplante/métodos
17.
J Hematol Oncol ; 8: 36, 2015 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-25886742

RESUMEN

NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity. Thus, the inhibition of TIM-3/Gal-9 immune check point, which affects NK cell-dependent IFNγ production and the consequent IDO1 activation, could usefully integrate current chemotherapeutic approaches.


Asunto(s)
Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/inmunología , Transducción de Señal/inmunología , Escape del Tumor/inmunología , Western Blotting , Células Cultivadas , Cromatografía Líquida de Alta Presión , Ensayo de Inmunoadsorción Enzimática , Galectinas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Interferón gamma/metabolismo , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Leucemia Mieloide Aguda/metabolismo , Proteínas de la Membrana/metabolismo
18.
J Transl Med ; 12: 240, 2014 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-25179788

RESUMEN

BACKGROUND: HLA-haploidentical hematopoietic stem cell transplantation (HSCT) is suitable for patients lacking related or unrelated HLA-matched donors. Herein, we investigated whether plerixafor (MZ), as an adjunct to G-CSF, facilitated the collection of mega-doses of hematopoietic stem cells (HSC) for TCR-αß/CD19-depleted haploidentical HSCT, and how this agent affects the cellular graft composition. METHODS: Ninety healthy donors were evaluated. Single-dose MZ was given to 30 'poor mobilizers' (PM) failing to attain ≥40 CD34+ HSCs/µL after 4 daily G-CSF doses and/or with predicted apheresis yields ≤12.0x106 CD34+ cells/kg recipient's body weight. RESULTS: MZ significantly increased CD34+ counts in PM. Naïve/memory T and B cells, as well as natural killer (NK) cells, myeloid/plasmacytoid dendritic cells (DCs), were unchanged compared with baseline. MZ did not further promote the G-CSF-induced mobilization of CD16+ monocytes and the down-regulation of IFN-γ production by T cells. HSC grafts harvested after G-CSF + MZ were enriched in myeloid and plasmacytoid DCs, but contained low numbers of pro-inflammatory 6-sulfo-LacNAc+ (Slan)-DCs. Finally, children transplanted with G-CSF + MZ-mobilized grafts received greater numbers of monocytes, myeloid and plasmacytoid DCs, but lower numbers of NK cells, NK-like T cells and Slan-DCs. CONCLUSIONS: MZ facilitates the collection of mega-doses of CD34+ HSCs for haploidentical HSCT, while affecting graft composition.


Asunto(s)
Enfermedades Hematológicas/terapia , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas , Compuestos Heterocíclicos/administración & dosificación , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Donantes de Tejidos , Aloinjertos , Antígenos CD19/metabolismo , Antígenos CD34/metabolismo , Bencilaminas , Tipificación y Pruebas Cruzadas Sanguíneas , Recuento de Células , Niño , Ciclamas , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Enfermedades Hematológicas/inmunología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/fisiología , Humanos
19.
Transfusion ; 54(12): 3145-54, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25041366

RESUMEN

BACKGROUND: Virus-specific CD4 and CD8 T lymphocytes from HLA-matched donors are effective for treatment and prophylaxis of viral infections in immune-compromised recipients of hematopoietic stem cell transplant recipients. Adoptive immune reconstitution is based on selection of specific T cells or on generation of specific T-cell lines from the graft donor. Unfortunately, the graft donor is not always immune to the relevant pathogen or the graft donor may not be available (registry-derived or cord blood donors). STUDY DESIGN AND METHODS: Since the possibility of using T cells from a third-party subject is now established, we screened potential donors for T-cell responses against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus, the viruses most frequently targeted by adoptive immune reconstitution. Specific T-cell responses against viral antigens were analyzed in 111 donors using a miniaturized interferon-γ release assay. RESULTS: Responders to CMV were 64%, to EBV 40%, and to adenovirus 51%. Simultaneous responders to the three viruses were 49%. CMV-specific CD4 and CD8 T-cell lines could be generated from 11 of 12 donors defined as positive responders according to the T-cell assay. CONCLUSIONS: These data demonstrate that a large fraction of volunteers can be recruited in a donor registry for selection or expansion of virus specific T cells and that our T-cell assay predicts the donors' ability to give rise to established T-cell lines endowed with proliferative potential and effector function for adoptive immune reconstitution.


Asunto(s)
Donantes de Sangre , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Infecciones por Virus ADN , Antígenos HLA/inmunología , Prueba de Histocompatibilidad , Huésped Inmunocomprometido , Inmunoterapia Adoptiva/métodos , Adulto , Antígenos Virales/inmunología , Bioensayo/métodos , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Infecciones por Virus ADN/inmunología , Infecciones por Virus ADN/terapia , Virus ADN/inmunología , Femenino , Humanos , Inmunidad Celular , Interferón gamma/inmunología , Masculino , Persona de Mediana Edad
20.
Blood ; 124(5): 822-6, 2014 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-24869942

RESUMEN

Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of αß(+) T cells and CD19(+) B cells. The median number of CD34(+), αß(+)CD3(+), and B cells infused was 16.8 × 10(6), 40 × 10(3), and 40 × 10(3) cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of γδ(+) T cells was prompt, but αß(+) T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120.


Asunto(s)
Linfocitos B , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Depleción Linfocítica , Receptores de Antígenos de Linfocitos T alfa-beta , Linfocitos T , Aloinjertos , Antígenos CD/metabolismo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Lactante , Masculino , Estudios Retrospectivos
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