The overall goal of this Program Project Grant is to develop regimens for allogeneic stem cell transplantation. That have minimal toxicity and are nonmyeloablative. Specifically, our goal is to replace the currently used intensive cytotoxic conditioning programs with immunosuppression aimed at controlling both host verssus-graft (HVG) and GVH reactions and establishing stable mixed donor-host hematopoietic chimerism. The novel transplant approach embraces the concepts that 1) stem cell grafts create their own marrow space through graft-versus-host (GVH) reactions, 2) regimens can be safe enough to be administered in the ambulatory care setting, and 3) toxicities can be low enough to allow inclusion of older patients currently not eligible for transplantation. Further, we hypothesize that mixed chimerism will be sufficient by itself to cure phenotypic expression of inherited hematological diseases and that mixed hematopoietic chimerism may serve as a platform for ~adoptive~ immunotherapy with donor lymphocyte infusions in patients with selected hematological malignancies. Three research projects and three cores are proposed. The first project will extend preliminary observations on mixed chimerism made in a preclinical canine model with the goals of developing the least toxic immunosuppresive regimens and of increasing the safety of donor lymphocyte infusions needed to convert mixed chimerism to complete chimerism. The second project will evaluate the application of mixed hematopoietic chimerism to the treatment of inherited canine and human red blood cell disorders. The third project will establish stable mixed chimerism after nonmyeloablative conditioning as a first therapeutic step for older patients with chronic myelocytic leukemia (66-74 years) and selected B-cell malignancies (50-65 years) who are at high risk of toxicity with conventional transplant regimens. This will be followed by donor lymphocyte infusions to convert mixed to full- donor chimerism and eradicate the underlying malignancy. All three projects will be supported by Core A with regard to protocol design, data monitoring and statistics. Core B will provide chimerism analyses and canine histocompatibility typing, and Core C will provide administrative support.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA078902-01A1
Application #
2833434
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
Project Start
1999-04-12
Project End
2004-01-31
Budget Start
1999-04-12
Budget End
2000-01-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
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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