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Blood Adv ; 3(14): 2057-2068, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31292125


Adoptive transfer of virus-specific T cells (VSTs) has been shown to be safe and effective in stem cell transplant recipients. However, the lack of virus-experienced T cells in donor cord blood (CB) has prevented the development of ex vivo expanded donor-derived VSTs for recipients of this stem cell source. Here we evaluated the feasibility and safety of ex vivo expansion of CB T cells from the 20% fraction of the CB unit in pediatric patients receiving a single CB transplant (CBT). In 2 clinical trials conducted at 2 separate sites, we manufactured CB-derived multivirus-specific T cells (CB-VSTs) targeting Epstein-Barr virus (EBV), adenovirus, and cytomegalovirus (CMV) for 18 (86%) of 21 patients demonstrating feasibility. Manufacturing for 2 CB-VSTs failed to meet lot release because of insufficient cell recovery, and there was 1 sterility breach during separation of the frozen 20% fraction. Delayed engraftment was not observed in patients who received the remaining 80% fraction for the primary CBT. There was no grade 3 to 4 acute graft-versus-host disease (GVHD) associated with the infusion of CB-VSTs. None of the 7 patients who received CB-VSTs as prophylaxis developed end-organ disease from CMV, EBV, or adenovirus. In 7 patients receiving CB-VSTs for viral reactivation or infection, only 1 patient developed end-organ viral disease, which was in an immune privileged site (CMV retinitis) and occurred after steroid therapy for GVHD. Finally, we demonstrated the long-term persistence of adoptively transferred CB-VSTs using T-cell receptor-Vß clonotype tracking, suggesting that CB-VSTs are a feasible addition to antiviral pharmacotherapy.

Pediatr Transplant ; 22(5): e13210, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29719098


Relapsed ALK-positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow-up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced-toxicity conditioning regimen containing fludarabine, alemtuzumab, and low-dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant-related complications were experienced. One patient developed chronic renal disease secondary to transplant-associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients' post-CRZ monotherapy, and further studies may be warranted.

Transplante de Células-Tronco Hematopoéticas , Linfoma Anaplásico de Células Grandes/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Criança , Crizotinibe , Feminino , Humanos , Masculino , Recidiva , Transplante Homólogo , Adulto Jovem
Behav Brain Res ; 319: 200-206, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-27851909


Cancer survivors diagnosed during infancy and adolescence may be at risk for chemotherapy-related cognitive impairments (CRCI), however the effects of pediatric chemotherapy treatment on adulthood cognitive function are not well understood. Impairments in memory, attention and executive function affect 15-50% of childhood leukemia survivors related to methotrexate exposure. Systemic cisplatin is used to treat a variety of childhood and adult cancers, yet the risk and extent of cognitive impairment due to platinum-based chemotherapy in pediatric patients is unknown. Systemic cisplatin penetrates the CNS, induces hippocampal synaptic damage, and leads to neuronal and neural stem/progenitor cell (NSC) loss. Survivors of non-leukemic cancers may be at risk for significant cognitive impairment related to cisplatin-driven neurotoxicity. We sought to examine the long-term effects of systemic cisplatin administration on cognitive function when administered during infancy and adolescence in a rat model. We performed cognitive testing in adult rats exposed to systemic cisplatin during either infancy or adolescence. Rats treated as adolescents showed significantly poor retrieval of a novel object as compared to controls. Further, cisplatin-treated infants and adolescents showed poor contextual discrimination as compared to controls, and an impaired response to cued fear conditioning. Ultimately, systemic cisplatin exposure resulted in more profound impairments in cognitive function in rats treated during adolescence than in those treated during infancy. Further, exposure to cisplatin during adolescence affected both hippocampus and amygdala dependent cognitive function, suggesting a more global cognitive dysfunction at this age.

Envelhecimento/efeitos dos fármacos , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Transtornos Cognitivos/induzido quimicamente , Fatores Etários , Animais , Condicionamento (Psicologia)/efeitos dos fármacos , Discriminação (Psicologia)/efeitos dos fármacos , Medo/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Recognição (Psicologia)/efeitos dos fármacos
J Clin Immunol ; 36(7): 725-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27539235


The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2). Limited data exist regarding the use of HSCT in patients with hypomorphic RAG variants marked by greater preservation of RAG activity and associated phenotypes such as granulomatous disease in combination with autoimmunity. We describe a 17-year-old with combined immunodeficiency and immune dysregulation characterized by granulomatous lung disease and autoimmunity secondary to compound heterozygous RAG mutations. A myeloablative reduced toxicity HSCT was completed using an unrelated bone marrow donor. With the increasing cases of immune dysregulation being discovered with hypomorphic RAG variants, the use of HSCT may advance to the forefront of treatment. This case serves to discuss indications of HSCT, approaches to preparative therapy, and the potential complications in this growing cohort of patients with immune dysregulation and RAG deficiency.

Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Doença Granulomatosa Crônica/complicações , Transplante de Células-Tronco Hematopoéticas , Proteínas de Homeodomínio/genética , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/terapia , Adolescente , Alelos , Doenças Autoimunes/diagnóstico , Biomarcadores , Doença Granulomatosa Crônica/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunofenotipagem , Infecção/diagnóstico , Infecção/etiologia , Infecção/terapia , Contagem de Linfócitos , Mutação , Imunodeficiência Combinada Severa/diagnóstico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo , Resultado do Tratamento
J Adolesc Young Adult Oncol ; 5(3): 226-31, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27078009


INTRODUCTION: The development of complex cognitive functions including executive functions occurs during adolescence and early young adulthood. Survivors of cancers diagnosed during adolescence and young adulthood (AYA) may be at specific risk for chemotherapy-associated cognitive impairment; however, little data are available that specifically examine long-term cognitive outcomes in the AYA-onset cancer survivor population. METHODS: A literature search was conducted between January 1991 to December 2015 using a variety of search terms pertaining to the AYA-onset cancer population and cognitive outcomes. Articles that described cognitive outcomes in AYA-onset cancer survivors without primary or secondary central nervous system lesions diagnosed at ages 14-25 years old were examined and reported. RESULTS: Three articles fulfilled the inclusion criteria. All three evaluated cognitive outcomes in AYA-onset cancer survivors at varying time points after receipt of systemic chemotherapy. Target groups and neuropsychological evaluation techniques differ across studies. All studies reported increased rates of objective or self-reported cognitive impairment in AYA-onset cancer survivors. DISCUSSION: AYA-onset cancer survivors experience cognitive impairment. Despite the nature of normal adolescent neurodevelopment, chemotherapy exposure during the AYA years may not significantly contribute to cognitive impairment. Chronic cognitive impairment may be associated with chronic complications of cancer therapy. Large-scale standardized, prospective, and longitudinal evaluations of cognitive outcomes specific to AYA-onset cancer survivor population are needed to better understand associated risk factors.

Neoplasias/mortalidade , Sobreviventes/psicologia , Adolescente , Adulto , Disfunção Cognitiva , Feminino , Humanos , Masculino , Neoplasias/psicologia , Fatores de Risco , Adulto Jovem