Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial

Abstract

The copper chelator tetraethylenepentamine (TEPA; StemEx) was shown to attenuate the differentiation of ex vivo cultured hematopoietic cells resulting in preferential expansion of early progenitors. A phase I/II trial was performed to test the feasibility and safety of transplantation of CD133 þ cord blood (CB) hematopoietic progenitors cultured in media containing stem cell factor, FLT-3 ligand, interleukin-6, thrombopoietin and TEPA. Ten patients with advanced hematological malignancies were transplanted with a CB unit originally frozen in two fractions. The smaller fraction was cultured ex vivo for 21 days and transplanted 24 h after infusion of the larger unmanipulated fraction. All but two units contained o2 Â 10 7 total nucleated cells (TNCs) per kilogram pre-expansion. All donor-recipient pairs were mismatched for one or two HLA loci. Nine patients were beyond first remission; median age and weight were 21 years and 68.5 kg. The average TNCs fold expansion was 219 (range, 2-620). Mean increase of CD34 þ cell count was 6 (over the CD34 þ cell content in the entire unit). Despite the low TNCs per kilogram infused (median ¼ 1.8 Â 10 7 /kg), nine patients engrafted. Median time to neutrophil and platelet engraftment was 30 (range, 16-46) and 48 (range, 35-105) days. There were no cases of grades 3-4 acute graft-versus-host disease (GVHD) and 100-day survival was 90%. This strategy is feasible.

Cord blood banking for clinical transplantation

“…Still, more innovative methods are being tried including the blocking of differentiation in stem and progenitor cells being grown in vitro by modulating the concentration of copper ions 40 and with specific enzymes that methylate DNA and others that acetylate histones. 41 In preparation for the eventual development of a useful expansion technique, however, we have developed a patented, two-compartment, 25 ml freezing bag, to allow culture of the small compartment (5 ml) without disrupting the continuous storage of the stem cells in the large compartment (20 ml) and there are many thousands of CBUs stored in such containers.…”

Ex vivo expansion of hematopoietic stem cells

“…The result showed that 90% of patients engrafted with no severe GVHD and a 90% 100-d survival. However, neither neutrophil nor platelet engraftment times were significantly improved [179].…”

Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?

“…This technology is expected to enter a phase 3 trial during this calendar year. 20 nicotinamide, or agents that indirectly affect such pathways, such as copper chelation 15 …”

“…13 Exposure of UCB progenitors to TEPA in cultures containing stimulatory cytokines (SCF, TPO, IL-6 and FLT-3 ligand) produced an 89-fold increase in CD34 þ cells, 14 which provided a scientific basis for a phase 1-2 clinical trial to test the feasibility and safety of TEPA-mediated HPC expansion. 15 In that study, a single UCB unit was divided, with one aliquot cultured in cytokine-enriched media containing TEPA for 21 days, which resulted in a 219-and 6-fold expansion of total nucleated cells and CD34 þ cells, respectively. Then expanded UCB progenitors were administered 24 h after infusion of the unmanipulated fraction of the same UCB unit to 10 patients who received myeloablative conditioning for various hematological malignances.…”