? PROJECT 1 Hematopoietic cell transplant (HCT) is the only curative therapy for certain nonmalignant hematologic and immunologic disorders, but the risks of the procedure, namely regimen-related toxicities and complications of graft-vs.-host disease (GVHD), are considered prohibitive for many patients. Previously our group has developed regimens that essentially eliminated the risk of regimen-related mortality for most patients given HLA-matched grafts. The overall goal of Project 1 is to introduce safe and effective HCT procedures for the most challenging patients with life-threatening nonmalignant disorders: 1) those with serious co-morbidities; 2) those with inherent resistance to engraftment, such as sickle cell anemia; and 3) those with HLA- mismatched grafts. In order to accomplish this goal, we propose practice-changing strategies to eliminate short- and long-term toxicities associated with the regimen, and GVHD associated with HLA-mismatched grafts.
In Specific Aim 1, we will investigate astatine-211 (211At)-anti-CD45 monoclonal antibody (MAb) to target conditioning directly to cells of the marrow and immune system. The short path length of the alpha-emitter, its very high energy, and short half-life, may reduce both early toxicities as well as late effects, such as secondary malignancies and infertility, associated with conventional conditioning agents. Non-toxic conditioning with 211At- anti-CD45 MAb will be developed for two groups of HLA-identical recipients: 1) primary immune deficiency syndromes complicated by life-threatening infections or co-morbidities, and 2) hemoglobinopathies such as sickle cell anemia or thalassemia. For patients without HLA-matched grafts, we tackle the challenge of establishing HLA-haploidentical grafts following nonmyeloablative conditioning. Accordingly, in Specific Aim 2 we seek to eliminate the risk of GVHD. We will test the hypothesis that suicide gene-modified AP1903- susceptible donor T cells (BPX 501) will aid CD34+-selected cell engraftment without the risk of GVHD.
In Specific Aim 3 we propose to incorporate 211At-anti-CD45 MAb to HLA-haploidentical grafts after nonmyeloablative conditioning, a goal particularly important for sickle cell anemia patients, who are more resistant to engraftment. Ultimately, we aim to combine targeted 211At-anti-CD45 MAb conditioning with CD34+ selected grafts with BPX 501 addback as a strategy to achieve engraftment without risk of either toxic effects or GVHD. If the strategies proposed in Project 1 are successful, we will remove the most prohibitive complications of HCT, thereby giving rise to a procedure accessible to more patients. The successful development of safe HLA-haploidentical transplantation would assure that virtually every patient with a candidate disease, especially patients from ethnic minority groups, could be treated.

Public Health Relevance

? PROJECT 1 Patients with life-threatening nonmalignant diseases, such as primary immune deficiencies, bone marrow failure, and sickle cell anemia, have disease-related factors that contribute to poor outcome after hematopoietic cell transplantation (HCT); therefore progress can be made only if these factors are taken into consideration. If the strategies proposed in Project 1 are successful, we will remove the most prohibitive complications of HCT thereby giving rise to a procedure accessible to nearly all patients with candidate diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL122173-01A1
Application #
8934997
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2015-07-15
Budget End
2016-05-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
Georges, George E; Doney, Kris; Storb, Rainer (2018) Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment. Blood Adv 2:2020-2028
Adair, Jennifer E; Chandrasekaran, Devikha; Sghia-Hughes, Gabriella et al. (2018) Novel lineage depletion preserves autologous blood stem cells for gene therapy of Fanconi anemia complementation group A. Haematologica 103:1806-1814
Thakar, M S; Bonfim, C; Walters, M C et al. (2017) Dose-adapted post-transplant cyclophosphamide for HLA-haploidentical transplantation in Fanconi anemia. Bone Marrow Transplant 52:570-573
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
Burroughs, Lauri M; Shimamura, Akiko; Talano, Julie-An et al. (2017) Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. Biol Blood Marrow Transplant 23:1669-1677
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
Shadman, Mazyar; Hingorani, Sangeeta; Lanum, Scott A et al. (2017) Allogeneic hematopoietic cell transplant for patients with end stage renal disease requiring dialysis - a single institution experience. Leuk Lymphoma 58:740-742
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

Showing the most recent 10 out of 21 publications