The central hypothesis of Project 1 is that a combination of umbilical cord blood (UCB)-derived T regulatory (Treg) cells and thymic progenitors (Tprog) will optimize the safety of UCB by eliminating the risk of severe acute GVHD and enhancing immune recovery. During the current funding period, we initiated the first-inhuman clinical trials with UCB Treg after having developed an expansion culture methodology that routinely yielded Treg that were highly suppressive both in vitro and in vivo using a xenogenic GVHD murine model. During this period, we also evaluated the effect of commonly used immunosuppressive agents on Treg at concentrations routinely achievable in transplant recipients. On the basis of these results, we initiated a second clinical trial with UCB-Tregs using rapamycin (Rapa) rather than Cyclosporin A in combination with mycophenolate mofetil (MMF) to optimize in vivo expansion and half life as well as potency. Over the next grant period, our goal is to develop an integrated, cell-based approach that will ultimately reduce the risk of acute GVHD, permit a reduction in the need for prolonged posttransplant immunosuppression, and enhance the pace of immune reconstitution. To accomplish these goals, we will first establish the maximum tolerable dose of Treg using newly developed improved methods for large scale Treg manufacture, and then demonstrate the potency of partially HLA matched Treg in prevention and ?off the shelf? HLA unmatched Treg in treatment of acute GVHD. We will also test novel approaches to T cell immune reconstitution by determining the optimal balance of Treg and T effector cells in the UCB graft without posttransplant GVHD prophylaxis, and subsequently adding Tprog to this treatment platform to enhance thymopoiesis and T cell immune reconstitution. At the conclusion of these studies, we will have demonstrated the safety profile and potency of UCB Treg and established a new treatment paradigm without pharmacologic immunosuppression for evaluating safety and efficacy of Tprog.

Public Health Relevance

Graft versus host disease and delayed immune reconstitution after allogeneic hematopoietic cell transplant result in considerable morbidity and mortality. T regulatory cells and thymic progenitor cells are capable of inducing tolerance and enhancing immune recovery, respectively. In a series of preclinical and clinical trials, we plan to optimize the clinical manufacture of these cell populations and demonstrate their safety and efficacy in the setting of umbilical cord blood transplantation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA065493-19
Application #
8533734
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
19
Fiscal Year
2013
Total Cost
$205,736
Indirect Cost
$98,538
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Turcotte, Lucie M; Yingst, Ashley; Verneris, Michael R (2016) Metabolic Syndrome after Hematopoietic Cell Transplantation: At the Intersection of Treatment Toxicity and Immune Dysfunction. Biol Blood Marrow Transplant 22:1159-66
Eckfeldt, Craig E; Randall, Nicole; Shanley, Ryan M et al. (2016) Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD. Haematologica 101:e348-51
Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin et al. (2016) Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 76:5696-5706
Pritchett, Joshua C; Green, Jaime S; Thomm, Angela M et al. (2016) CD4+ T Cells Coexpressing CD134 (OX40) Harbor Significantly Increased Levels of Human Herpesvirus 6B DNA Following Umbilical Cord Blood Transplantation. J Infect Dis 214:1911-1915
Trottier, B J; Sachs, Z; DeFor, T E et al. (2016) Novel disease burden assessment predicts allogeneic transplantation outcomes in myelodysplastic syndrome. Bone Marrow Transplant 51:199-204
Brinkman, C Colin; Iwami, Daiki; Hritzo, Molly K et al. (2016) Treg engage lymphotoxin beta receptor for afferent lymphatic transendothelial migration. Nat Commun 7:12021
Brunstein, Claudio G; Miller, Jeffrey S; McKenna, David H et al. (2016) Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood 127:1044-51
Nakamura, Ryotaro; La Rosa, Corinna; Longmate, Jeffrey et al. (2016) Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial. Lancet Haematol 3:e87-98
Omer, Aazim K; Weisdorf, Daniel J; Lazaryan, Aleksandr et al. (2016) Late Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 22:879-83
Knorr, David A; Wang, Hongbo; Aurora, Mukta et al. (2016) Loss of T Follicular Helper Cells in the Peripheral Blood of Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 22:825-33

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