A Novel Therapy for Sickle Cell Disease (SCD): Co-Transplantation of Nicord® [Ex Vivo Expanded Umbilical Cord Blood (UCB) Progenitor Cells with Nicotinamide] and an Unmanipulated Unrelated UCB Graft Leads to Successful Engraftment and Cure of Severe SCD

Allogeneic hematopoietic stem cell transplant (HSCT) is currently the only curative therapy for sickle cell disease (SCD) patients, but many do not have access to matched donors. Unrelated cord blood (UCB) can be an alternative graft option but, to date, HSCT with a single UCB unit has resulted in high rates of graft failure (GF). NiCord is an ex vivo expanded product manufactured from an entire UCB unit, shown to produce rapid and sustained engraftment in combination with a second unmanipulated (UM) UCB unit or as a standalone graft in adults with hematologic malignancies. We hypothesized that combination of NiCord with an UM UCB unit might overcome the engraftment barrier in SCD patients and explored this strategy in a phase I/II multi-center study in pediatric SCD patients undergoing myeloablative HSCT. We report results of the first 11 patients enrolled in the study. Patients with severe SCD and adequate organ function were eligible if they were between 2 - 45 years of age and had 2 suitable unrelated UCB units that minimally matched the patient at 4/6 HLA alleles. The NiCord graft consisted of a CD133+ expanded cell fraction and an uncultured CD133- T-cell containing fraction. Patients received hydroxyurea from day -35, followed by myeloablative chemotherapy. The first 3 patients received Busulfan/Cyclophosphamide/Anti Thymocyte Globulin (ATG). For the next 8 patients, ATG was replaced by Fludarabine. On day 0, the UM UCB and NiCord grafts were infused. Eleven patients were transplanted at a median age of 11.8 (range 3.4-16.9) years. HLA matching between patients and NiCord units was 4/6 (n = 10) and 5/6 (n = 1); between patients and UM units was 4/6 (n = 8) and 5/6 (n = 3). Median CD34+ cell dose infused in the NiCord graft was 124x 105/kg. All 11 patients initially engrafted neutrophils at a median of 7 (range 6-20) days (10/11 with the NiCord graft). Ultimately, long-term engraftment was derived from NiCord (n = 2), UM unit (n = 7) and sustained mixed chimerism (n = 1). One patient engrafted on day 9, had secondary GF on day 13 and died after a 2nd transplant. Eight patients had grade II-IV acute GVHD (grade II = 5, III-IV = 3); 2 extensive chronic GVHD. One patient died on day +241 from liver GVHD. Nine of the 10 patients with sustained full donor chimerism are alive and disease-free at a median f/u of 22 (6.3-58) months with 1 year event-free survival of 77.9% (95%CI 35.4%, 94.2%). None of the surviving patients had active GVHD at last follow up. NiCord appears to overcome the engraftment barrier of UCB in SCD patients. Sustained donor cell engraftment was achieved in 10/11 patients, despite 4/6 matched UCB units and 8 patients without ATG. Further optimization of this approach with strategies to further decrease GVHD is warranted. Transplantation of SCD patients with NiCord as a standalone graft will be explored. NiCord has the potential to increase access to transplantation for SCD patients by enabling use of unrelated UCB donors.