RESUMEN
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.
Asunto(s)
Neuroblastoma , Receptores Quiméricos de Antígenos , Niño , Adulto Joven , Humanos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Proteómica , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfocitos T , Neuroblastoma/patología , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
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.
