- PROJECT 1 A recent comprehensive analysis of outcomes among the first 1,092 patients with advanced hematologic malignancies transplanted under the auspices of current Projects 2 and 3 showed that one-fifth of patients died of graft-vs.-host disease (GVHD)-related causes. The analysis further showed that acute GVHD had no statistically significant associations with GVT effects. This suggested that avoiding acute GVHD would reduce the risk of non-relapse mortality (NRM) without increasing the risk of relapse. In contrast, chronic GVHD was highly significantly associated with GVT effects;however, this benefit was offset by NRM, which was largely due to infections occurring during the lengthy period of treatment for chronic GVHD. So the challenge is not to prevent chronic GVHD, since that might increase the risk of relapse, but to treat it more effectively so that both the duration of treatment and the associated risks of morbidity and NRM are reduced while GVT effects are maintained. The proposed studies will use a DLA-mismatched canine hematopoietic cell transplantation (HCT) model that has a long-standing track record of translating novel acute GVHD prevention and treatment into the clinic. Moreover, we have now established the only simple, reproducible, and clinically relevant large animal model of chronic GVHD. Having reproducible models of both acute GVHD and of chronic GVHD places us in a unique position to better understand, treat, and prevent GVH reactions. In these two canine models, T-cell activation occurs as it does clinically in human patients, despite standard postgrafting immunosuppression, which then results in either acute or chronic GVHD. Linked mechanistic studies will tell us about unique phenotypic and functional T-cell signatures that will be predictive of quiescence or of GVHD and might be targets of therapeutic interventions. In the current funding period, we have developed a unique set of canine- specific monoclonal antibodies (mAbs) and fusion proteins interacting with regulatory cell-surface determinants on T-cells that hold promise of enabling more-specific interventions in immune responses than have been possible with current pharmacological immunosuppression. We expect to be guided in the proposed therapeutic studies by mechanistic studies which might determine the time of upregulation of T-cell-specific antigens that have: ? Costimulatory function which may be blocked; ? Down-regulatory function that can be activated;or ? No regulatory function, but which can be used as targets for radioimmunotherapy. We believe that the proposed rational use of biologic agents to prevent acute GVHD and to treat chronic GVHD is highly novel and, moreover, that therapy successful in the canine model can be translated to benefit human patients transplanted under the auspices of Projects 2 and 3.

Public Health Relevance

- PROJECT 1 This project is focused on preventing and treating potentially fatal immunological side effects that can occur after transplantation of marrow or blood stem cells in the treatment of patients with malignant diseases. The studies will be conducted in a large, preclinical animal model, which has a long track record of developing novel therapies that can be translated into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA078902-16
Application #
8742470
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2000-03-31
Project End
2019-08-31
Budget Start
2014-09-02
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
$627,064
Indirect Cost
$256,955
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Green, Margaret L; Leisenring, Wendy; Xie, Hu et al. (2016) Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 3:e119-27
Aki, S Z; Inamoto, Y; Carpenter, P A et al. (2016) Confounding factors affecting the National Institutes of Health (NIH) chronic Graft-Versus-Host Disease Organ-Specific Score and global severity. Bone Marrow Transplant 51:1350-1353
Rosinski, Steven Lawrence; Stone, Brad; Graves, Scott S et al. (2016) Minor Antigen Vaccine-Sensitized DLI: In Vitro Responses Do Not Predict In Vivo Effects. Transplant Direct 2:e71
Hoffmeister, P A; Storer, B E; Syrjala, K L et al. (2016) Physician-diagnosed depression and suicides in pediatric hematopoietic cell transplant survivors with up to 40 years of follow-up. Bone Marrow Transplant 51:153-6
Cassaday, Ryan D; Alan Potts Jr, D; Stevenson, Philip A et al. (2016) Evaluation of allogeneic transplantation in first or later minimal residual disease - negative remission following adult-inspired therapy for acute lymphoblastic leukemia. Leuk Lymphoma 57:2109-18
Johnston, Christine; Harrington, Robert; Jain, Rupali et al. (2016) Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant 22:149-56
Storb, Rainer; Sandmaier, Brenda M (2016) Nonmyeloablative allogeneic hematopoietic cell transplantation. Haematologica 101:521-30
Crews, Leslie A; Balaian, Larisa; Delos Santos, Nathaniel P et al. (2016) RNA Splicing Modulation Selectively Impairs Leukemia Stem Cell Maintenance in Secondary Human AML. Cell Stem Cell 19:599-612
Khera, Nandita; Gooley, Ted; Flowers, Mary E D et al. (2016) Association of Distance from Transplantation Center and Place of Residence on Outcomes after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 22:1319-23
Mielcarek, Marco; Furlong, Terry; O'Donnell, Paul V et al. (2016) Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA-matched mobilized blood cell transplantation. Blood 127:1502-8

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