StemRegenin-1 (SR1) Expansion Culture Abrogates the Engraftment Barrier Associated with Umbilical Cord Blood Transplantation (UCBT)

Background. The use of UCB has been substantially limited by the low finite number of CD34+ cells, resulting in prolonged periods of cytopenia and high risk of graft failure, restricting its widespread application particularly for adults. SR1 is an aryl hydrocarbon receptor antagonist that enables CD34 cell proliferation in the presence of SCF, Flt-3L, IL-6 and TPO without differentiation. Therefore, we tested the safety and efficacy SR1 expanded UCB (referred to as ‘HSC835’).

Patients and Methods: Patients with high-risk hematologic malignancy were enrolled in a Phase 1/2 dose escalation study. All were treated with cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and total body irradiation 1320 cGy with cyclosporine and mycophenolate mofetil post-transplant immune suppression. Seventeen patients received HSC835 along with its CD34 depleted fraction and an unmanipulated UCB unit and two patients thus far received HSC835 as a stand-alone graft.

Results: For the first 17, SR-1 expansion culture yielded a median of 1,440 x 10⁶ CD34+ cells (range, 140.2-6361.9) as compared to the input number of 4.4 x 10⁶ (range, 2.1-15.6) after CD34 selection – a 328-fold (range, 65.9-844.0) expansion of CD34+ cells. Relative to recipients of a standard double UCB graft without manipulation (n=111) containing a median of 0.5 x 10⁶ CD34+ cells/kg (0.1-2.1) with 87% engraftment, HSC835-treated patients received a median of 12.3 x 10⁶ CD34+ cells/kg (2.3-48.5) with 100% engraftment. Of the 11/17 patients in whom the HSC835 predominated, neutrophils recovered at a median of 11 days (6-23) as compared to 23 days (14-30) for those in whom the unmanipulated unit predominated (Figure). Similarly, as compared to the 111 double UCBT controls, both neutrophil and platelet recoveries were remarkably shortened in HSC835 recipients (p<0.001 and p=0,001, respectively). Importantly, chimerism was stable 0.4-2 years out. Single unit chimerism in all lineages was derived from HSC835 in six and the unmanipulated unit in six. However, stable dual myeloid chimerism was observed in 5 with T cells completely derived from the unmanipulated unit. Interestingly, neutrophil recovery occurred faster in those with dual myeloid chimerism at a median of 7 days (6-10) (Figure, o) as compared to those with single myeloid chimerism (·). 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, and not by HSC exhaustion, as evidenced by absence of late graft failures or marked change in telomere length (10.5Kb to 10Kb). Therefore the subsequent study will evaluate the safety and efficacy of HSC835 as a sole source. Thus far, 2 have been treated with promising early engraftment results. Receiving doses of 25 and 18 x 10⁶ CD34/kg, neutrophil recovery was observed on day 12 and 8, respectively.

Conclusion: HSC835 dramatically accelerates hematopoietic recovery, abrogating the principal barrier to the successful use of UCB. Such impressive CD34+ expansion potentially heralds a paradigm shift for both UCB transplantation and cord blood banking. With such high CD34+ cell doses, all patients will have an adequate single UCB unit with an improved chance of identifying a 5-6/6 HLA matched unit since the entire UCB inventory will be available irrespective of weight. Furthermore, units with cell counts <1 billion nucleated cells should no longer be discarded, crucial for improving collection efficiencies, and increasing the size of the registry, particularly important for enhancing representation of ethnic/racial minority populations.

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