John Wagner, M.D., Stem Cell Institute at the University of Minnesota

wagne002@umn.edu

RESEARCH INTERESTS

To date, research has been focused on the translational development of novel somatic cell therapies to treat of a variety of life threatening lympho-hematopoietic disorders and to reduce the immunological complications of allogeneic hematopoietic stem cell transplantation.  Large-scale development of counterflow elutriation as a method of separating stem and progenitor cells from alloreactive lymphocytes moved from small single center phase I-II testing to a large multi-institutional national trial completed in 2001.  More recent investigations have been focused on expanding the application of HLA mismatched umbilical cord blood as a new source of hematopoietic stem cells for treating adults and children. 

After definitively demonstrating the relationship of cell dose and engraftment and survival, work has been directed to determining new strategies for overcoming the barrier of cell dose. In 2001, phase I-II clinical trials were initiated to test the safety and potential efficacy of:

1. Co-transplantation of mesenchymal stem cells with umbilical cord blood,

2. Transplantation of two partially HLA matched umbilical cord blood units,

3. Transplantation of umbilical cord blood after immunosuppression alone without myeloablation. 

In addition, a novel strategy was explored to address the association between HLA disparity and transplant-related mortality, namely, the use of in vitro fertilization and preimplantation genetic diagnosis to identify which embryo would be HLA matched with the affected sibling. 

In 2000, the success of this approach was demonstrated in a child with Fanconi anemia - the "Molly Nash case".. This approach has been used successfully in numerous couples who have a child with sickle cell disease, thalassemia, Blackfan Diamond anemia, leukemia, etc., providing them with an unaffected child that is HLA identical with the child that could potentially benefit from umbilical cord blood transplantation.

Research into the pathophysiology and treatment of Fanconi anemia is also ongoing.  This work, in collaboration with staff of the Fanconi Anemia Comprehensive Clinic at the University of Minnesota and investigators at Rockefeller University (Auerbach), Oregon Health Sciences University (Grompe, Bagby), Dana Farber Cancer Institute (D’Andrea) and others, has led to new discoveries in diagnosis and treatment.  Research at the University is currently focused on reducing transplant-related mortality, such as with thymic shielding to enhance immune reconstitution and infusion of the multipotent adult stem cell to repair chemotherapy and radiation-injured tissues after hematopoietic cell transplantation.

As director of the Center of Molecular and Cellular Therapeutics, the development of methods for large-scale production of biological reagents is another research focus.   In 2003, the University of Minnesota was awarded a contract from the NHLBI as a national resource to assist in the development of new somatic cell therapies for clinical testing.

SPECIFIC PROJECTS

1.  Umbilical Cord Blood Transplantation in Children and Adults

• Ex vivo expansion of hematopoietic stem cells

• Double unit transplantation

• Non-myeloablative preparative therapies

• Preimplantation genetic diagnosis to select HLA identical embryo

• Development of UCB-derived effector cell therapies: natural killer cells and regulatory T-cells

2.  Fanconi Anemia

• Novel preparative therapies

• Gene therapy - hematopoietic stem cells, multipotent adult progenitor cells

• Phenotype-genotype correlations

• Somatic mosaisms:  mechanisms and clinical outcomes

3.  Multipotent Adult Progenitor Cells (MAPC)

• Translational development/large scale manufacture of MAPC

• Evaluation of MAPC therapeutic potential in congenital and acquired disorders

• Development of animal model/animal MAPC cell banks

SELECTED RECENT PUBLICATIONS

• McCullough J, McKenna D, Kadidlo D, Schierman T, Wagner JE.  Issues in the Quality of Umbilical Cord Blood (UCB) Stem Cells for Transplantation.  Transfusion. 45:832-841  (2005).
• Wagner JE, Kahn JP, Wolf SM, Lipton FM.  Preimplantation Testing to Produce an HLA Matched Donor Infant.  JAMA 292:803-804 (2004).
• Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney S, Yun G, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB.  Successful Adoptive Transfer and InVivo Expansion of Human Haploidentical NK Cells in Cancer Patients.  Blood. 105:3051-7 (2005).
• Cornetta K, Laughlin M, Carter S, Wall D, Weinthal J, Sievers E, Wagner JE,Sweetman R, McCarthy P, Jensen, L, Nelson C. Umbilical Cord Blood Transplantation in Adults: Results of the Prospective Cord Blood Transplantation (COBLT). Biol Blood Marrow Transplant. 11:149-60 (2005).
• Barker J, Hough RE, van Burik J, DeFor T, MacMillan ML, O’Brien MR, Wagner JE. Serious Infections After Unrelated Donor Transplantation in 136 Children: Impact of Stem Cell Source.  Biol  Blood Marrow Tranplant. 11:362-70 (2005).
• Wagner JE, Thompson JS, Carter SL, Kernan NA.  Effect of Graft-versus-Host Disease Prophylaxis on 3-Year Disease Free Survival in Recipients of Unrelated Donor Bone Marrow Transplantation: Results of a Multi-Center, Randomized Phase II-III Trial. Lancet. 366:733-41 (2005).
• McCullough J, Miller J, Wagner JE, Kadidlo D, Orchard P.  The Minnesota Molecular and Cellular Therapeutics Facility: A State-of-the-Art Biotherapeutics Engineering Laboratory.  Transfusion Medicine Reviews.  19:217-228 (2005).
• Tan PL, Wagner JE, Auerbach AD, Defor TE, MacMillan ML, Slingaard A. Successful Engraftment  Without Radiation after Fludarabine-Based Regimen in Fanconi Anemia Patients Undergoing Genotypically Identical Donor Hematopoietic Cell Transplantation. Pediatr Blood Cancer. 00:1-7 (2005).
• van Burik, JH, Carter SL, Freifeld AG, High KP, Godder KT, Papanicolaou GA, Mendizabal AM,Wagner JE, Yanovich S, Kernan NA.   Analysis of Infectious Complications After Unrelated Donor Bone Marrow Transplantation: Part II, Results of a Prospective Multi-center Trial Comparing T-Cell Depletion Versus Immune Suppression Therapy.  J. Clin Oncology. In Press (2005).
• Wall DA, Carter SL, Kernan NA, Kapoor N, Kamani NR, Brochstein JA, Frangoul H, Goyal RK, Horan JT, Pietryga D, Wagner JE, Kurtzberg J, on behalf of COBLT Steering Committee.  Busulfan/Melphalan/ATG Followed by Unrelated Donor Cord Blood Transplantation for Treatment of Infant Leukemia and Leukemia in Young Children: the COBLT Experience.  Biol Blood Marrow Transplant.  8:637-46 (2005).
• Fraser CJ, Hirsch BA, Dayton V, Creer MH, Neglia JP, Wagner JE, Baker KS. First Report of Donor Cell Derived Acute Leukemia as a Complication of Umbilical Cord Blood Transplantation.  Blood. DOI 10.1182/blood-2005-06-2551.
• Grewal SS, Wagner JE.   Umbilical Cord Blood Transplantation. Pediatric Stem Cell Transplantation,Eds. Kline R:  Medicine Jones & Bartlett Publishers.  In Press (2005).
• MacMillan ML, Wagner JE.  Hematopoietic Cell Transplantation for Congential Bone Marrow Failure. Curr Opin Oncol. 17:106-13 (2005).
• Martin PL, Carter, SL, Kernan NA, Sahdev I, Wall D, Pietryga D, Wagner JE, Kurtzberg J.  Results of the Cord Blood Transplantation Study (COLBT): Transplant Outcomes of Unrelated Donor Umbilical Cord Blood Transplantation in Pediatric Patients With Lysosomal and Peroxisomal Storage Diseases.Biol Blood Marrow Transplant.  In Press (2006).
• Porter SB, Liu B, Rogosheske J, Levine BL, June CH, Kohl VK, Wagner JE, Miller JS, Blazar BR.  Suppressor Function of Umbilical Cord Blood (UCB) Derived CD4⁺CD25⁺ T-Regulatory (Treg) Cells Exposed to Graft-Versus-Host Disease (GVHD) Drugs.  Transplantation.  In Press (2006).
• Eapen M, Rubinstein P, Zhang MJ, Camitta B, Stevens C, Cairo MS, Davies SM, Doyle JJ, Kurtzberg J, Pulsipher MA, Ortega JJ, Scaradavou A, Horowitz MM, Wagner JE. Comparable Long-Term Survival After Unrelated and HLA-Matched Sibling Hematopoietic Stem Cell Transplants for Acute Leukemia in Children Less Then 18 Months. J. Clin Oncology. 24:145-151 (2006).