The goal of this Program is to broaden the application and further the success of allogeneic hematopoietic cell transplantation (HCT) for treatment of patients with cancer. The work will focus on HCT approaches in which the burden of tumor eradication has been shifted from high-dose conditioning regimens to the donors' immune cells. Minimally toxic, nonmyeloablative, yet, immunosuppressive conditioning has replaced the myeloablative and toxic doses of chemotherapeutic agents customarily administered with or without high-dose total body irradiation. After HCT, control of residual host-vs.-graft and graft-vs.-host reactions is achieved by relatively brief courses of synergistic postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The immunosuppressive regimen originated from studies in dogs and has been successfully used to treat patients with advanced hematological malignancies. Significantly, the low degree of regimen-related toxicity has enabled us to use allogeneic HCT in elderly patients and those with medical infirmities. Given that median patient ages at diagnoses for most candidate diseases range from 65-70 years, this has greatly expanded the number of patients benefiting from allogeneic HCT, and during the first 3 1/2 years of the grant, 439 patients have been transplanted. Four Research Projects and three Cores are proposed. Project 1 will focus on developing new non-toxic transplant approaches, with the aim of eliminating the last vestiges of cytotoxic therapy. Project 2 will use the canine model of stable mixed chimerism to develop clinically relevant approaches of effective adoptive immunotherapy with donor lymphocytes. The clinical Projects 3 and 4 will extend the current trials by developing disease-specific protocols for patients with leukemia's, multiple myelomas, Hodgkin's disease, non-Hodgkin lymphoma, and renal cell cancer. This way, we intend to obtain a better understanding of effectiveness and limitations of graft-vs.-tumor reactions in the various candidate diseases. Appropriate conditioning regimens will be defined, as will be the duration of postgrafting immunosuppression. Studies will be conducted with a consortium of collaborators, including 10 institutions outside of Seattle. All four projects will be supported by Cores with regard to protocol design, data monitoring and statistics, chimerism analyses and canine histocompatibility typing, and will provide administrative support.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA078902-07
Application #
6890022
Study Section
Subcommittee G - Education (NCI)
Program Officer
Merritt, William D
Project Start
2000-03-31
Project End
2009-01-31
Budget Start
2005-02-10
Budget End
2006-01-31
Support Year
7
Fiscal Year
2005
Total Cost
$2,009,048
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807
Maffini, Enrico; Anderson Jr, Larry D; Sandmaier, Brenda M et al. (2018) Non-myeloablative allogeneic hematopoietic cell transplantation for relapsed or refractory Waldenström macroglobulinemia: evidence for a graft-versus-lymphoma effect. Haematologica 103:e252-e255
Li, Yawen; Hamlin, Donald K; Chyan, Ming-Kuan et al. (2018) cGMP production of astatine-211-labeled anti-CD45 antibodies for use in allogeneic hematopoietic cell transplantation for treatment of advanced hematopoietic malignancies. PLoS One 13:e0205135
Bar, Merav; Flowers, Mary E D; Storer, Barry E et al. (2018) Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial. Biol Blood Marrow Transplant 24:308-313
Graves, Scott S; Parker, Maura H; Stone, Diane et al. (2018) Anti-Inducible Costimulator Monoclonal Antibody Treatment of Canine Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:50-54
Hill, Joshua A; Mayer, Bryan T; Xie, Hu et al. (2017) The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 129:2316-2325
Venkataraman, G M; Kennedy, L J; Little, M-T E et al. (2017) Thirteen novel canine dog leukocyte antigen-88 alleles identified by sequence-based typing. HLA 90:165-170
McDonald, George B; Tabellini, Laura; Storer, Barry E et al. (2017) Predictive Value of Clinical Findings and Plasma Biomarkers after Fourteen Days of Prednisone Treatment for Acute Graft-versus-host Disease. Biol Blood Marrow Transplant 23:1257-1263
Hill, Joshua A; Magaret, Amalia S; Hall-Sedlak, Ruth et al. (2017) Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. Blood 130:1062-1069
Green, Damian J; Maloney, David G; Storer, Barry E et al. (2017) Tandem autologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance therapy for high-risk myeloma. Blood Adv 1:2247-2256

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