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

Allogeneic stem cell transplantation with umbilical cord blood (UCB) cells is limited by the cell dose a single unit provides recipients. Ex vivo expansion is one strategy to increase the number of cells available for transplantation. Aastrom Biosciences developed an automated continuous perfusion culture device for expansion of hematopoietic stem cells (HSCs). Cells are expanded in media supplemented with fetal bovine serum, horse serum, PIXY321, flt-3 ligand, and erythropoietin. We performed a phase 1 trial augmenting conventional UCB transplants with ex vivo-expanded cells. The 28 patients were enrolled on the trial between October 8, 1997 and September 30, 1998. UCB cells were expanded in the device, then administered as a boost to the conventional graft on posttransplantation day 12. While expansion of total cells and colony-forming units (CFUs) occurred in all cases, the magnitude of expansion varied considerably. The median fold increase was 2.4 (range, 1.0-8.5) in nucleated cells, 82 (range, 4.6-266.4) in CFU granulocyte-macrophages, and 0.5 (range, 0.09-2.45) in CD34+ lineage negative (lin-) cells. CD3+ cells did not expand under these conditions. Clinical-scale ex vivo expansion of UCB is feasible, and the administration of ex vivo-expanded cells is well tolerated. Augmentation of UCB transplants with ex vivo-expanded cells did not alter the time to myeloid, erythroid, or platelet engraftment in 21 evaluable patients. Recipients of ex vivo-expanded cells continue to have durable engraftment with a median follow-up of 47 months (range, 41-51 months). A randomized phase 2 study will determine whether augmenting UCB transplants with ex vivo-expanded UCB cells is beneficial.

[1]  J. Adamson,et al.  Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[2]  C. Chastang,et al.  Outcome of cord-blood transplantation from related and unrelated donors , 1997 .

[3]  M S Pepe,et al.  Kaplan-Meier, marginal or conditional probability curves in summarizing competing risks failure time data? , 1993, Statistics in medicine.

[4]  G. Ehninger,et al.  Defining Optimum Conditions for the Ex Vivo Expansion of Human Umbilical Cord Blood Cells. Influences of Progenitor Enrichment, Interference with Feeder Layers, Early‐Acting Cytokines and Agitation of Culture Vessels , 1999, Stem cells.

[5]  W. Piacibello,et al.  HEMATOPOIESIS Engraftment in Nonobese Diabetic Severe Combined Immunodeficient Mice of Human CD 34 1 Cord Blood Cells After Ex Vivo Expansion : Evidence for the Amplification and Self-Renewal of Repopulating Stem Cells , 1999 .

[6]  J. Adamson,et al.  Outcomes among 562 recipients of placental-blood transplants from unrelated donors. , 1998, The New England journal of medicine.

[7]  M. Koller,et al.  Clinical-scale human umbilical cord blood cell expansion in a novel automated perfusion culture system , 1998, Bone Marrow Transplantation.

[8]  L. Lajtha,et al.  Conditions controlling the proliferation of haemopoietic stem cells in vitro , 1977, Journal of cellular physiology.

[9]  E. Shpall,et al.  Autologous transplantation of ex vivo expanded bone marrow cells grown from small aliquots after high-dose chemotherapy for breast cancer. , 2000, Blood.

[10]  E. Shpall,et al.  Ex-vivo expansion of bone marrow progenitor cells for hematopoietic reconstitution following high-dose chemotherapy for breast cancer. , 1999, Experimental hematology.

[11]  C. Chastang,et al.  Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. , 1997, The New England journal of medicine.

[12]  Manfred R. Koller,et al.  Ex Vivo Hematopoietic Cell Expansion for Bone Marrow Transplantation , 1999 .

[13]  E. Shpall,et al.  Transplantation of adult and pediatric cancer patients with cord blood progenitors expanded ex vivo , 2000 .

[14]  M. Koller,et al.  Long-term culture-initiating cell expansion is dependent on frequent medium exchange combined with stromal and other accessory cell effects. , 1995, Blood.

[15]  Lesley J. Murray,et al.  Thrombopoietin, kit ligand, and flk2/flt3 ligand together induce increased numbers of primitive hematopoietic progenitors from human CD34+Thy-1+Lin- cells with preserved ability to engraft SCID-hu bone. , 1998, Blood.

[16]  H. Mayani,et al.  Kinetics of Hematopoiesis in Dexter‐Type Long‐Term Cultures Established from Human Umbilical Cord Blood Cells , 1998, Stem cells.

[17]  Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. , 1996, The New England journal of medicine.

[18]  J. Klein,et al.  Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. , 2000, The New England journal of medicine.

[19]  Robert E. Nordon,et al.  Ex vivo cell therapy , 1999 .

[20]  J. Wagner,et al.  Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease. , 1996, Blood.

[21]  F Locatelli,et al.  Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group. , 1999, Blood.

[22]  J. Adamson,et al.  Stored placental blood for unrelated bone marrow reconstitution. , 1993, Blood.

[23]  H. Kaplan,et al.  Long-term culture of human bone marrow cells. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[24]  E D Thomas,et al.  1994 Consensus Conference on Acute GVHD Grading. , 1995, Bone marrow transplantation.

[25]  Thomas O. Toole,et al.  Hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood progenitor cells evaluated in vitro and in vivo. , 1996, Blood.

[26]  J. Wagner,et al.  Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. , 1997, Blood.

[27]  M. Koller,et al.  Bioreactor expansion of human bone marrow: comparison of unprocessed, density-separated, and CD34-enriched cells. , 1995, Journal of hematotherapy.

[28]  S. Emerson,et al.  Large-scale expansion of human stem and progenitor cells from bone marrow mononuclear cells in continuous perfusion cultures. , 1993, Blood.

[29]  J. Wagner,et al.  Cord Blood Transplantation Study (COBLT): cord blood bank standard operating procedures. , 1998, Journal of hematotherapy.