- PROJECT 2 High-dose chemoradiotherapy conditioning before allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with advanced myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who have failed conventional chemotherapy;however, allogeneic HCT produces a 5-year survival rate of only 20-30%.as a result of non-relapse mortality and, especially, relapse. Prior studies in younger patients have shown that increasing the dose of total body irradiation prior to HCT significantly reduces the relapse rate but increases regimen-related toxicity, negating the advantage of the lower relapse rate. Moreover, most patients with AML or MDS are older than 60 years and unable to tolerate high-dose conditioning. As an alternative to high-dose conditioning, we have explored the use of beta-emitters - iodine-131 and yttrium-90 conjugated with our anti-CD45 monoclonal antibody - as an adjunct strategy to deliver targeted radiation to hematolymphoid tissues and disease sites while minimizing toxicity to normal organs. However, the long path length, long half-life, and relatively low energy of these radioisotopes may not provide enough targeted radiation and still have off-target effects. An attractive alternative to the beta-emitters is the use of alpha-emitting radionuclides. The short path length, very high energy, high cytotoxicity of alpha-emissions, and short half-life may generate effective tumor cell kill while avoiding early toxicities as well as late effects, such as secondary cancers, associated with conventional systemic conditioning agents including beta-emitters. We propose the use of the alpha-emitter astatine-211 (211At), which is short-lived and provides high-energy radiation, conjugated to our anti-CD45 antibody as part of an HCT conditioning regimen for patients with advanced AML, ALL or high-risk MDS.
Specific Aim 1 will investigate the 211At-labeled anti-CD45 antibody as an adjunct to a well-tolerated reduced-intensity conditioning regimen for human leukocyte antigen (HLA)- matched related or unrelated HCT. Furthermore, there remains a critical need to extend the option of HCT as potential therapy of hematologic malignancies to patients who do not have a readily available HLA-matched donor, a problem especially acute for patients in ethnic minority groups. In these cases, donors would be HLA- haploidentical relatives. The current HLA-haploidentical HCT conditioning regimen, while well tolerated, has a relapse rate of 47% at 1 year. Therefore, Specific Aim 2 proposes the addition of 211At-labeled anti-CD45 antibody to the conditioning regimen for HLA-haploidentical HCT to improve disease control for advanced AML, ALL, and high-risk MDS in patients without substantially increasing the toxicity. We believe that our extensive preclinical experience using alpha-emitters combined with our preclinical and clinical experience with beta- emitters predicts a high likelihood of success.

Public Health Relevance

- PROJECT 2 This project is focused on reducing the risk of relapse of malignancy in patients with advanced acute leukemia or myelodysplasia who have been treated with stem cell transplantation from healthy donors. We propose to accomplish this goal by using targeted radiation with an antibody to the cancer cell coupled to a short-lived radioactive isotope.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA078902-16
Application #
8742471
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
$153,120
Indirect Cost
$68,118
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

Showing the most recent 10 out of 322 publications