Augmentation of umbilical cord blood (UCB) transplantation with ex vivo–expanded UCB cells: results of a phase 1 trial using the AastromReplicell System

Jaroscak, Jennifer Joi; Goltry, Kristin L.; Smith, Alan K.; Waters‐Pick, Barbara; Martin, Paul L.; Driscoll, Timothy A.; Howrey, Richard P.; Chao, Nelson J.; Douville, Judith; Burhop, Sue; Fu, Pingfu; Kurtzberg, Joanne

doi:10.1182/blood-2001-12-0290

Cited by 278 publications

(175 citation statements)

References 28 publications

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“…This approach involves expansion of UCB in cytokines in vitro prior to infusion [51][52][53]. Early clinical trials based on infusion of a proportion of the UCB graft expanded ex vivo in cytokine-based conditions have failed to demonstrate more rapid hematopoietic recovery in UCB recipients, suggesting that cytokine based expansion may result in differentiation of early self-renewable stem cells.…”

Section: Ucb Basic Biology and Implications For Hematopoietic Reconstmentioning

confidence: 99%

“…Early clinical trials based on infusion of a proportion of the UCB graft expanded ex vivo in cytokine-based conditions have failed to demonstrate more rapid hematopoietic recovery in UCB recipients, suggesting that cytokine based expansion may result in differentiation of early self-renewable stem cells. Reports from the Duke University program have shown that infusion of ex-vivo expanded UCB did not alter the time to myeloid, erythroid or platelet engraftment [53]. Shpall et al reported their experience at the University of Colorado with infusion of ex vivo expanded cells along with the UCB [51].…”

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

151

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: Ucb Basic Biology and Implications For Hematopoietic Reconstmentioning

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

151

112

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“…16,17 Strategies aimed at improving engraftment and reducing TRM in UCBT recipients, such as infusion of two units in the same recipient, ex vivo expansion of UCB HSCs and intrabone injection of cord blood cells, have been recently proposed. [18][19][20] Besides these approaches, the co-infusion of MSCs together with UCB HSCs could be an alternative option for optimizing the engraftment of donor cells. Indeed, MSCs, which are multipotent cells capable of differentiation into several mesenchymal lineages, 21,22 possess peculiar properties of immunomodulation on all cells involved in the immune response.…”

Section: Introductionmentioning

confidence: 99%

Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation

Bernardo

Ball

Cometa

et al. 2010

Bone Marrow Transplant

159

120

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When compared with BMT, umbilical cord blood transplantation (UCBT) is associated with a lower rate of engraftment and delayed hematological/immunological recovery. This leads to increased risk of TRM in the early post transplantation period due to infection. Acute GVHD, although occurring less frequently in UCBT compared with BMT, is also significantly associated with increased rate of early TRM. BM MSCs are known to support normal in vivo hematopoiesis, and co-transplantation of MSCs has been shown to enhance engraftment of human cord blood hematopoietic cells in nonobese diabetic/SCID mice. In 13 children with hematological disorders (median age 2 years) undergoing UCBT, we cotransplanted paternal, HLA-disparate MSCs with the aim of improving hematological recovery and reducing rejection. We observed no differences in hematological recovery or rejection rates compared with 39 matched historical controls, most of whom received G-CSF after UCBT. However, the rate of grade III and IV acute GVHD was significantly decreased in the study cohort when compared with controls (P ¼ 0.05), thus resulting in reduced early TRM. Although these data do not support the use of MSCs in UCBT to support hematopoietic engraftment, they suggest that MSCs, possibly because of their immunosuppressive effect, may abrogate life-threatening acute GVHD and reduce early TRM.

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“…We estimate that no more than 1,000 expanded HSPCs transplantations were successfully performed in the world, some of which were used in patients with solid malignant tumors. Jaroscak et al performed a phase 1 trial in which conventional UCB transplants were augmented 12 days later with UCB cells expanded in an automated continuous perfusion culture device [59]. Long-term follow-up (ranged from 41 to 51 months) showed that the patients transplanted with ex vivoexpanded cells continued to have durable engraftment.…”

Section: Clinical Applicationmentioning

confidence: 99%

Expansion of hematopoietic stem/progenitor cells

Deng

Duan

2008

American J Hematol

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Hematopoietic stem/progenitor cells (HSPCs) transplantation is hampered by the low number of stem cells per sample. To tackle this obstacle, several protocols for expansion of HSPCs in vitro are currently in development, such as the use of cytokine cocktails, coculture with mesenchymal stem cells as feeder cells, and cell culture in bioreactors. With the progress in the understanding of the molecular and cellular mechanisms regulating HSPCs maintenance and expansion, more recent approaches have involved transcription regulation, cell cycle regulation, telomerase regulation, and chromatin-modifying agents. The potential clinical application and safety issues relevant to the expanded HSPCs are also discussed in this review. Am. J. Hematol. 83:922-926, 2008. V

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Augmentation of umbilical cord blood (UCB) transplantation with ex vivo–expanded UCB cells: results of a phase 1 trial using the AastromReplicell System

Cited by 278 publications

References 28 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

Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation

Expansion of hematopoietic stem/progenitor cells

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