Abstract 15 Safety of DUOC-01, Intrathecal Cord Blood-Derived Cellular Therapy, as an Adjunct to Allogeneic Cord Blood Transplantation in Children with Inherited Metabolic Diseases

Abstract

IntroductionUnrelated donor umbilical cord blood transplantation (CBT) improves function and extends life in children with certain inherited metabolic diseases (IMDs); however, progressive neurologic decline often occurs during the few months post-CBT prior to donor engraftment in the brain, causing residual, irreversible impairments. We previously described donor engraftment in the brain after CBT and developed DUOC-01, a monocyte-derived CB cell product, to attempt to accelerate donor cell delivery to the brain.ObjectiveThe objective of this study was to determine manufacturing feasibility and safety of intrathecal DUOC-01 in a phase I study in children with IMDs undergoing CBT after myeloablative cytoreduction (busulfan/cyclophosphamide/anti-thymocyte globulin).MethodsDUOC-01 was manufactured in adherent cell culture in a GMP lab over 21 days with a target dose of ≤100 × 105 cells. When cell dose permitted, 80% of the CB unit was used for transplant and 20% of the same unit was used to manufacture DUOC-01. Otherwise, DUOC-01 was manufactured from a unique CB unit. On day ≥+28 post-CBT, if there was evidence of hematopoietic engraftment without severe graft versus host disease or morbidity, DUOC-01 cells were harvested and administered intrathecally. Safety was monitored via neurologic exams, neuroimaging, and CSF studies.ResultsForty patients (aged 0-15 years) underwent CBT, 37 engrafted with donor cells. Median infused total nucleated cell count was 6.5 × 107/kg (range 2.9-33.1 × 107/kg); median time to neutrophil engraftment was 20 days (range 13-46 days). Ten patients did not receive DUOC-01 cells for the following reasons: engraftment failure (3), transplant-related morbidity (4), and low manufacturing yield (3). Thirty patients received 0.2-100 × 105 DUOC-01 cells intrathecally for a median of 31 days (range 27-77 days) post-CBT (19 with the same CB donor and 11 with a unique CB donor). Two patients developed transient fever and hypotension hours after unique-donor DUOC-01, consistent with an inflammatory response. Hydrocortisone (HC) was added to the final formulation, and post-validation, seven additional patients received unique-donor DUOC-01+HC without incident. No other DUOC-01-related serious adverse events occurred.DiscussionDUOC-01 is a CB-derived product intended to accelerate donor cell delivery to the brain of children with IMDs undergoing CBT. Intrathecal DUOC-01 administration is well-tolerated post-CBT from the same donor and, with the addition of HC, also from a unique donor. Escalating DUOC doses are being tested for safety and exploration of potential efficacy in a phase Ia trial of adults with multiple sclerosis.