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1.
J Allergy Clin Immunol ; 144(1): 280-293, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30731121

RESUMO

BACKGROUND: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks. OBJECTIVE: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies. METHODS: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T-cell receptor (TCR) αß/CD19-depleted grafts, 43 cord blood (CB) grafts (72% with no serotherapy), 17 CD34+ selection with T-cell add-back grafts, and 65 unmanipulated grafts. RESULTS: The estimated 8-year survival of the entire cohort was 79%, transplant-related mortality was 21.7%, and the graft failure rate was 6.7%. Posttransplantation viral reactivation, grade II to IV acute graft-versus-host disease (aGvHD), and chronic graft-versus-host disease (cGvHD) complicated 49.6%, 35%, and 15% of transplantations, respectively. Use of TCRαß/CD19 depletion was associated with a significantly lower incidence of grade II to IV aGvHD (11.5%) and cGvHD (0%), although with a greater incidence of viral reactivation (70%) in comparison with other grafts. T-cell immune reconstitution was robust among CB transplants, although with a high incidence (56.7%) of grade II to IV aGvHD. Stable full donor engraftment was significantly greater at 80% among TCRαß+/CD19+-depleted and CB transplants versus 40% to 60% among the other groups. CONCLUSIONS: Rapidly accessible CB and haploidentical grafts are suitable alternatives for patients with no HLA-matched donor. Cord transplantation without serotherapy and TCRαß+/CD19+-depleted grafts produced comparable survival rates of around 80%, although with a high rate of aGvHD with the former and a high risk of viral reactivation with the latter that need to be addressed.

2.
Cytotherapy ; 20(6): 830-838, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29753677

RESUMO

BACKGROUND: Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity. METHOD: This study was an open-label phase 1/2 study to investigate the feasibility of generating donor-derived ADV-specific T cells (Cytovir ADV, Cell Medica) and to assess the safety of pre-emptive administration of ADV-specific T cells in high-risk pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT) to treat adenoviremia. Primary safety endpoints included graft-versus-host disease (GvHD), and secondary endpoints determined antiviral responses and use of antiviral drugs. RESULTS: Between January 2013 and May 2016, 92 donors were enrolled for the production of ADV T cells at three centers in the United Kingdom (UK), and 83 products were generated from 72 mobilized peripheral blood harvests and 20 steady-state whole blood donations. Eight children received Cytovir ADV T cells after standard therapy and all resolved ADV viremia between 15 and 127 days later. ADV-specific T cells were detectable using enzyme-linked immunospot assay (ELISpot) in the peripheral blood of all patients analyzed. Serious adverse events included Grade II GvHD, Astrovirus encephalitis and pancreatitis. CONCLUSION: The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.


Assuntos
Infecções por Adenoviridae/prevenção & controle , Adenoviridae/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Infecções por Adenoviridae/complicações , Infecções por Adenoviridae/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/virologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular , Lactente , Masculino , Fatores de Risco , Linfócitos T/imunologia , Imunologia de Transplantes , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Ativação Viral/imunologia
3.
Sci Transl Med ; 9(374)2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28123068

RESUMO

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19+ B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfócitos T/citologia , Nucleases dos Efetores Semelhantes a Ativadores de Transcrição/genética , Alemtuzumab/uso terapêutico , Antígenos CD19/metabolismo , Antígeno CD52/metabolismo , Ensaios de Uso Compassivo , Feminino , Edição de Genes , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Lentivirus/genética , Recidiva Local de Neoplasia , Receptores de Antígenos de Linfócitos T/genética , Indução de Remissão , Transplante de Células-Tronco , Efetores Semelhantes a Ativadores de Transcrição , Transplante Homólogo
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