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1.
Cancer Cell ; 42(1): 35-51.e8, 2024 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-38134936

RESUMO

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.


Assuntos
Neuroblastoma , Receptores de Antígenos Quiméricos , Criança , Adulto Jovem , Humanos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos de Linfócitos T/genética , Proteômica , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Linfócitos T , Neuroblastoma/patologia , Terapia Baseada em Transplante de Células e Tecidos
2.
Front Immunol ; 12: 801281, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975916

RESUMO

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.


Assuntos
Transferência Adotiva/efeitos adversos , Vírus BK/patogenicidade , Cistite/terapia , Síndrome da Liberação de Citocina/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hemorragia/terapia , Infecções por Polyomavirus/terapia , Linfócitos T/transplante , Infecções Tumorais por Vírus/terapia , Adolescente , Vírus BK/imunologia , Cistite/diagnóstico , Cistite/imunologia , Cistite/virologia , Síndrome da Liberação de Citocina/diagnóstico , Evolução Fatal , Hemorragia/diagnóstico , Hemorragia/imunologia , Hemorragia/virologia , Humanos , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/virologia , Resultado do Tratamento , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/virologia
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