Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine

Peled, Tony; Mandel, Julie; Goudsmid, R. N.; Landor, Chana; Hasson, Nira; Harati, Dorit; Austin, Melissa A.; Hasson, Arik; Fibach, Eitan; Shpall, Elizabeth J.; Nagler, Arnon

doi:10.1080/14653240410004916

Cited by 108 publications

(72 citation statements)

References 23 publications

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“…It was also reported that mature osteoblasts derived from an immortalized HM3-B10 MSC line can induce better expansion of multipotent progenitors (MPP), as determined in a long-term culture initiating cell (LTC-IC) assay (Mishima et al 2010). Both growth factor secretions and cell-cell contact have been reported to be needed for the growthmodulatory activates of MSC on HSPC (Flores-Guzman et al 2013;Peled et al 2004;Amsellem et al 2003). Moreover, coculture of HSPC in MSC contact-based cocultures has been shown to improve human chimerism after transplantation (Ferreira et al 2012;Goncalves et al 2006;Walenda et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

et al. 2016

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Engraftment outcomes are strongly correlated with the numbers of hematopoietic stem and progenitor cells (HSPC) infused. Expansion of umbilical cord blood (CB) HSPC has gained much interest lately since infusion of expanded HSPC can accelerate engraftment and improve clinical outcomes. Many novel protocols based on different expansion strategies of HSPC and their downstream derivatives are under development. Herein, we describe the production and properties of serum-free medium (SFM) conditioned with mesenchymal stromal cells derivedosteoblasts (OCM) for the expansion of umbilical CB cells and progenitors. After optimization of the conditioning length, we show that OCM increased the production of human CB total nucleated cells and CD34 ? cells by 1.8-fold and 1.5-fold over standard SFM, respectively. Production of immature CD34 ? subpopulations enriched in hematopoietic stem cells was also improved with a shorter conditioning period. Moreover, we show that the growth modulatory activities of OCM on progenitor expansion are regulated by both soluble factors and non-soluble cellular elements. Finally, the growth and differentiation modulatory activities of OCM were fully retained after high dose-ionizing irradiation and highly stable when OCM is stored frozen. In summary, our results suggest that OCM efficiently mimics some of the natural regulatory activities of osteoblasts on HSPC and highlight the marked expansion potentials of SFM conditioned with osteoblasts.

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Section: Introductionmentioning

confidence: 99%

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

et al. 2016

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“…11 Most importantly, the percentage of engrafted human progenitor cells as well as that of myeloid and lymphoid cells was reproducibly and significantly superior in SCID mice transplanted with TEPA-mediated ex vivo expanded cells than mice transplanted with similar numbers of cells expanded with the cytokine cocktail without TEPA, or with the corresponding cell fraction before expansion. 12,13 Based on these preclinical studies, we conducted a phase I/II clinical trial to test the safety of StemEx, a product containing an expanded portion of a CB unit, cultured for 21 days with early acting cytokines and the copper chelator TEPA, in combination with the remaining, unmanipulated portion of the same unit.…”

Section: Introductionmentioning

confidence: 99%

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

Lima

McMannis

Gee

et al. 2008

Bone Marrow Transplant

241

177

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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.

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“…NAM-mediated expansion resulted to a median 82-fold increase in the CD34 þ cell dose. Neutrophil engraftment was robust at a median time of 10 days (range [7][8][9][10][11][12][13][14] and durable with no increased toxicity. There were no graft failures and long-term engraftment was obtained from the expanded unit (authors' personal communications).…”

Section: Cord Blood Graft Enhancement M Norkin Et Almentioning

confidence: 95%

“…Cellular copper reduction in the presence of the copper chelator tetraethylenepentamine (TEPA) results in delays in progenitor differentiation and promotes expansion of cord blood-derived CD34 þ cells in cytokinesupplemented liquid medium. 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.…”

Section: Cord Blood Graft Enhancement M Norkin Et Almentioning

confidence: 99%

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

Norkin

Lazarus

Wingard

2012

Bone Marrow Transplant

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Umbilical cord blood (UCB) is an attractive stem cell graft option for patients who need allogeneic hematopoietic stem cell support, but lack a suitable HLA-matched donor. However, the limited number of hematopoietic progenitor cells in a single cord blood unit can lead to an increased risk of graft failure, delayed hematological recovery and prolonged immunosuppression, particularly in adult patients. Several strategies to overcome these potential limitations are being evaluated. In this review, we discuss promising ex vivo manipulations to enhance cord blood engraftment capacity such as culture of UCB cells with stimulatory cytokines and growth factors, mesenchymal cells, Notch ligand, copper chelators, prostaglandins, complement components, nicotinamide and CD26/DPPIV inhibitors. All these approaches are now in early clinical trials. However, despite the fact that several cord blood enhancement strategies have resulted in increased numbers of progenitor cells and faster neutrophil recovery, the ability of these techniques to significantly shorten engraftment time and permit the use of cord units with low numbers of total nucleated cells, or accomplish reliable engraftment with a single cord, have yet to be convincingly demonstrated. The ultimate clinical value of ex vivo cord blood expansion or manipulation has not been defined yet, and the current data do not permit predicting which technology will prove to be the optimal strategy. Nevertheless, expectations remain high that eventually ex vivo enhancement will be able to improve clinical outcomes and significantly extend the applicability of UCB transplantation.

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Pre-clinical development of cord blood-derived progenitor cell graft expanded ex vivo with cytokines and the polyamine copper chelator tetraethylenepentamine

Cited by 108 publications

References 23 publications

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

Characterization of the growth modulatory activities of osteoblast conditioned media on cord blood progenitor cells

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

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

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