? 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Fred Hutchinson Cancer Research Center
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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
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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
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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
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

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