The theme of this program has not changed in 15 years: Understanding the biology of human hematopoietic stem cells (HSC) and their progeny will result in improved hematopoietic cell-based therapy for a variety of lethal malignant diseases. In the current funding period we have established """"""""double umbilical cord blood"""""""" (DUCB) transplantation as an effective treatment which may transform the practice of hematopoietic cell transplantation (HCT) because it vastly increases the pool of patients to whom transplant can be offered. We will now approach three important issues in the DUCB transplant setting-graft versus host disease (GVHD), delayed immune reconstitution with resultant late infection, and refractory or relapsed leukemia. John Wagner MD and his co-investigator Bruce Blazar MD have generated preclinical data demonstrating the suppressive effect of UCB-derived regulatory T cells (Treg) on GVHD and performed """"""""first-in-human"""""""" UCB Treg safety and dose-finding trials. In Project 1, Dr Wagner proposes a series of clinical trials testing the efficacy of UCB Treg to prevent and to treat acute GVHD including add-back of UCB Tregs and effector T cells (Teffs) in calibrated doses, and development of """"""""off-the-shelf UCB Treg products. Dr Blazar has characterized UCB-derived progenitor T cells (Tprogs), and in Project 2 proposes basic studies exploring their role in restoration of thymic epithelial cell (TEC) function as well as inducible pluripotent stem cell (iPS) models to replace TEC. Findings from these studies will be translated in clinical trials conducted in Project 1 assessing the safety and efficacy of UCB Tprog therapy to reconstitute immune function following transplant and to reduce late, intracellular infections. Finally, in studies supported by this program, Jeffrey Miller MD has confirmed the marked anti-leukemia effects of allogeneic natural killer (NK) cells. In Project 3 he proposes pre-clinical and clinical studies of haplo-identical NK cell adoptive therapy used in combination with DUCB transplant to provide both immediate tumor reduction and long-term anti-leukemia effects in patients with refractory or relapse acute leukemia. These interactive projects are supported by administrative and biostatistical cores (A and B), as well as Core C, providing cGMP cell processing and immune monitoring and Core D, providing animals, environment and expertise to support human adoptive transfer experiments. This long-standing and highly collaborative program project is well positioned to examine these intertwined immunologic and clinical issues and to develop improved cell-based therapies for a variety of lethal hematologic malignancies.

Public Health Relevance

The cumulative results of our current and proposed programmatic studies will be to increase the availability, safety and efficacy of hematopoietic cell transplant and cell-based therapies to treat otherwise lethal hematopoietic malignancies. Findings from the proposed studies can also be used to treat other potentially fatal cancers, hematopoietic, immune, metabolic and infectious disorders, and to address current barriers to solid organ transplant in children and adults world-wide.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA065493-18S1
Application #
8494126
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (J1))
Program Officer
Ogunbiyi, Peter
Project Start
1997-09-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$65,073
Indirect Cost
$22,262
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Taraseviciute, Agne; Tkachev, Victor; Ponce, Rafael et al. (2018) Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates. Cancer Discov 8:750-763
Felices, Martin; Lenvik, Alexander J; McElmurry, Ron et al. (2018) Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 3:
Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775
Williams, Robin L; Cooley, Sarah; Bachanova, Veronika et al. (2018) Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells. Biol Blood Marrow Transplant 24:618-622
Don Yun, Hyun; Felices, Martin; Vallera, Daniel A et al. (2018) Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells. Blood Adv 2:1580-1584
Hippen, Keli L; Loschi, Michael; Nicholls, Jemma et al. (2018) Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease. Front Immunol 9:57
Pennell, Christopher A; Barnum, Jessie L; McDonald-Hyman, Cameron S et al. (2018) Human CD19-Targeted Mouse T Cells Induce B Cell Aplasia and Toxicity in Human CD19 Transgenic Mice. Mol Ther 26:1423-1434
Williams, Shelly M; Sumstad, Darin; Kadidlo, Diane et al. (2018) Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58:1458-1467
Mathew, Nimitha R; Baumgartner, Francis; Braun, Lukas et al. (2018) Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nat Med 24:282-291
Romee, Rizwan; Cooley, Sarah; Berrien-Elliott, Melissa M et al. (2018) First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131:2515-2527

Showing the most recent 10 out of 395 publications