Phase I Trial of Allogeneic Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells in Neonates with Hypoxic-Ischemic Encephalopathy

Background & Aim Background In neonatal animal models of hypoxic-ischemic brain injury administration of mesenchymal stromal cells (MSCs) improves anatomic and functional outcomes. A prior study suggests potential benefit of autologous cord blood-derived cells for infants with hypoxic-ischemic encephalopathy (HIE) but cord blood collection in this population is challenging. A safe, effective off-the-shelf allogeneic cell product could be a useful alternative. Our aim was to conduct a phase I open-label study of umbilical cord tissue-derived MSCs in infants treated with hypothermia for HIE. Methods, Results & Conclusion Methods Infants >35 weeks gestation treated with hypothermia for HIE based on NICHD hypothermia trial criteria were eligible. Goal enrollment was 6 infants. Allogeneic umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) were manufactured in the Robertson GMP Cell Manufacturing Laboratory from a single cord tissue donated to the Carolinas Cord Blood Bank. Cells were expanded to passage 2 and cryopreserved. A representative cryobag was quality-tested for cell count, viability, phenotype, functional assays, gram stain and sterility. For administration cells were thawed and diluted 1:1 and delivered in syringes containing plasmalyte-A, 5% HSA, and residual DMSO. Post thaw samples were tested for cell count, viability (required ≥70%) and sterility. The first 3 infants (cohort 1) received 2 × 106 cells/kg i.v. in the first 48 postnatal hours, the second 3 (cohort 2) received a 2nd dose at 2 months. Primary safety outcomes were occurrence of infusion reactions or infections within 2 weeks of infusion. Results Of 18 eligible infants, 6 were enrolled (Table 1). All cultures obtained from subjects were negative, and no subject had an infusion reaction. Subject #5, had a positive panel reactive antibody (PRA) screen at 6 months. Broth culture from thawed hCT-MSC for subject # 1 grew coagulase-negative staphylococci. The infant remained asymptomatic after re-warming and the infant's blood cultures were sterile. The broth culture was assessed as contaminant via handling post-thaw rather than cell product contamination. There was one protocol deviation (One infant received a study dose at 71 hours. (Table 2)). Conclusions Our results suggest that hCT-MSC, an umbilical cord tissue-derived MSC product, can be prepared and infused safely in infants treated with hypothermia for moderate - severe HIE. Further safety and efficacy studies are warranted.