Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice

Peled, Tony; Landau, Efrat; Mandel, Julie; Glukhman, Elina; Goudsmid, Noga Rosenheimer; Nagler, Arnon; Fibach, Eitan

doi:10.1016/j.exphem.2004.03.002

Cited by 116 publications

(72 citation statements)

References 25 publications

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“…Such "stroma free" systems are more adaptable for clinical use by avoiding complications from murine feeder cells. Ex vivo expansion of UCB cells to facilitate engraftment and immune reconstitution continues to be an area of active investigation [22].…”

Section: Transplantation With Ucb : Clinical Studiesmentioning

confidence: 99%

“…Thus, other characteristics of UCB progenitor cells may be responsible for the delayed engraftment of UCB stem cells. Such characteristics may include adhesion molecules, homing properties and maturational stage of UCB progenitor cells [22,[47][48][49]. These factors may have a major contribution in the kinetics and efficiency of engraftment and may explain why CD34 quantification in UCB has not been consistently predictive of time to hematopoietic reconstitution.…”

Section: Ucb Basic Biology and Implications For Hematopoietic Reconstmentioning

confidence: 99%

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Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

Brown

Boussiotis

2008

Clinical Immunology

152

112

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Allogeneic stem cell transplantation has continued to evolve as a common procedure for the treatment of hematological malignancies and bone marrow failure. Donor bone marrow and mobilized peripheral stem cells are routinely employed for the reconstitution of immune function in leukemia and lymphoma patients following radiation and/or chemotherapy. Unfortunately, only 30% of patients have an HLA identical sibling donor and the identification of matched unrelated donors, particularly for minorities, can present an exceptional challenge. The transplantation of umbilical cord blood (UCB) represents the most recent strategy to expand the potential donor pool while maintaining an acceptable level of treatment related complications. First utilized in children, UCB transplantation permits a higher degree of HLA disparity while demonstrating a reduction in the incidence and severity of graft versus host disease (GvHD) compared to previous transplantation modalities. Despite the apparent decrease in GvHD, relapse rates remain comparable to transplantation with bone marrow or mobilized peripheral blood suggesting a strong graft versus leukemia/lymphoma (GvL) effect. However, several issues complicate the use of UCB transplantation and its extension to the treatment of adults. Many infections that afflict transplant patients are particularly frequent and more severe in the context of UCB transplantation. UCB T cells are naïve and therefore display less proliferation and IFN-γ production in response to cognate antigen and also appear to demonstrate defects in signal transduction mechanisms. In addition, UCB contain T regulatory cells (Treg) with more potent suppressor function than adult Treg. Furthermore, adult patients often require more total cells and CD34+ progenitors for transplantation than a single UCB unit can provide. Thus, strategies to expand selected subpopulations from UCB and the use of multiunit transplantation are areas of active research. This review will provide a condensed summary of the clinical history of UCB transplantation and emphasize the advantages and disadvantages of this approach to hematological malignancies in comparison to other methods of hematopoietic stem cell transplantation. Subsequently, it will mainly focus on the current challenges to immune reconstitution presented by UCB transplantation, recent research into their cellular and molecular mechanisms, and experimental approaches to overcome them.

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Section: Transplantation With Ucb : Clinical Studiesmentioning

confidence: 99%

Section: Ucb Basic Biology and Implications For Hematopoietic Reconstmentioning

confidence: 99%

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

Brown

Boussiotis

2008

Clinical Immunology

152

112

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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

178

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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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“…Explorations into CB expansion and multiple CB unit transplants are addressing the limited cell doses attainable with a single CB collection. [1][2][3][4] At this point, one must conclude that bigger is better when selecting CB units for transplantation. …”

mentioning

confidence: 99%

Selection of cord blood unit(s) for transplantation

Wall

Chan

2008

Bone Marrow Transplant

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Selection of cord blood (CB) units for transplantation involves combining both cell dose and HLA matching as independent yet overlapping variables. Cell dose and cell yield at the time of transplant are critical given that the transplants are being performed with minimal cells for reliable engraftment. In transplants for malignant disorders, the greater allogenicity and lower relapse rate associated with the less well-matched units balance any benefit of better HLA matching on TRM. The only factor that has repeatedly been associated with improved outcome post CB transplant is cell dose. The CB inventories are rapidly increasing in size and the quality of CB units being banked (larger, better characterized) is improving. With this, some of our current limitations in CB availability will soon become moot. Explorations into CB expansion and multiple CB unit transplants are addressing the limited cell doses attainable with a single CB collection. [1][2][3][4] At this point, one must conclude that bigger is better when selecting CB units for transplantation.

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Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice

Cited by 116 publications

References 25 publications

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

Umbilical cord blood transplantation: Basic biology and clinical challenges to immune reconstitution

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

Selection of cord blood unit(s) for transplantation

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