Acceleration of Umbilical Cord Blood (UCB) Stem Engraftment: Results of a Phase I Clinical Trial with Stemregenin-1 (SR1) Expansion Culture

UCB has been substantially limited by the low finite number of CD34+ cells, resulting in slow hematopoietic recovery and poor engraftment. SR1 is an aryl hydrocarbon receptor antagonist that enables CD34 cell proliferation in the presence of SCF, Flt-3L, IL-6 and TPO. Therefore, we tested the safety and efficacy SR1-expanded UCB (referred to as ‘HSC835').  Nineteen patients (pts) with high-risk hematologic malignancy have been treated with HSC835 after myeloablative conditioning (cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and TBI 1320 cGy) with CsA and MMF post-transplant immune suppression. The first 17 received an unmanipulated second ‘back-up' UCB unit. SR-1 expansion culture yielded a median of 1,440 x 10⁶ CD34+ cells (range, 140.2-6361.9), a 328-fold (range, 65.9-844.0) expansion of CD34+ cells, for a median infused dose of 12.3 x 10⁶ CD34+ cells/kg (2.3-48.5). As shown (Figure), all patients engrafted with the HSC835 unit predominating in 11/17 at a median of 11 days for neutrophils (6-23). As expected, unit predominance was determined by graft-graft immune reactions, as evidenced by the presence of interferon-γ producing T cells directed against the losing graft. Chimerism in HSC835 engrafted patients was stable long term with no episode of late graft failure. Compared to 111 identically treated DUCB transplant historical controls without expanded cells (conventional arm), neutrophil and platelet recovery was remarkably shortened in HSC835 recipients (p<0.001 and p=0.001, respectively). Based on these data, a second trial with HSC835 as a stand-alone graft was initiated. In two patients, receiving 25 and 18 x 10⁶ CD34/kg, neutrophil recovery was rapid (days 12 and 8, respectively) and complete (100% chimerism). In summary, HSC835 dramatically accelerates hematopoietic recovery, abrogating the principal barrier to the successful use of UCB. Such impressive CD34+ expansion may lead to a paradigm shift for both UCB transplantation and banking.