- OVERALL The overall goal of this program project grant is to overcome disease relapse, which is the single-most important limitation of allogeneic hematopoietic cell transplant (HCT) in the treatment of older or medically infirm patients with myeloid malignancies and myeloma. Two principal approaches are proposed, understanding and enhancing graft-vs-tumor (GVT) effects after HCT and reducing the pre-HCT tumor burden by intensifying the conditioning regimen through innovative, first-in-human radioimmunotherapy (RIT) that has been entirely developed in our laboratories. Project 1 will lead to an understanding of how to enhance GVT effects using studies in a in vivo murine model and in a human in vitro model. Enhancing GVT effects will likely become an effective means of reducing the relapse problem. Projects 2 and 3 will employ novel first-in-human RIT technology using alpha- emitter astatine-211 (211At) conjugated to monoclonal antibodies that was first developed in murine and large animal models. This is now applied clinically in Phase I/II trials in patients with myeloid malignancies who have pre-HCT tumor including refractory disease and in patients with multiple myeloma. The principle addressed here is reducing the pre-transplant tumor burden, thereby shifting the balance in favor of the transplanted allogeneic donor lymphocytes. While RIT with an antibody to CD45, as proposed in Project 1, has been tolerated well in the ongoing dose-escalation trial, we expect that liver toxicity will be dose-limiting for myeloid malignancies. In order to get around that problem and to further minimize the toxicity profile of targeted RIT directed against CD45, Project 1 proposes to develop fully anti-human CD45 MAbs, with a series of MAb isotypes/variants, and then test the hypothesis that in vivo off-target toxicity of the RIT can be further minimized and 211At-anti-CD45 RIT be optimized by engineering of the MAb Fc portion to remove the potential to interact with Fc receptors, especially in the liver. Clinical trials in Project 3 will begin with a CD38 target for RIT and will next optimize the approach by switching to a B-cell maturation antigen (BCMA) target in order to achieve better efficacy of myeloma cell kill. In summary, work on the three projects will use a two-pronged approach at decreasing post-HCT relapse rates among patients with myeloid malignancies and multiple myeloma, reducing the pre-HCT tumor burden and enhancing post-HCT tumor kill through GVT effects. The outcomes of these studies have obvious bearings on allogeneic HCT in older patients with other hematologic malignancies.

Public Health Relevance

- Overall Life-threatening cancers of the blood system, such as leukemia, myelodysplasia and multiple myeloma, occur most frequently in older individuals. These diseases can be cured with hematopoietic cell transplantation from healthy donors, however, 30% - 60% of patients have their disease come back after transplant. Our goal is to improve the outcomes with minimal-intensity conditioning transplant by developing targeted therapy to reduce relapse risks.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA078902-22
Application #
10025198
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Henderson, Lori A
Project Start
1999-04-12
Project End
2025-06-30
Budget Start
2020-09-21
Budget End
2021-06-30
Support Year
22
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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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
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Luft, Thomas; Benner, Axel; Jodele, Sonata et al. (2017) EASIX in patients with acute graft-versus-host disease: a retrospective cohort analysis. Lancet Haematol 4:e414-e423
Graves, Scott S; Rezvani, Andrew; Sale, George et al. (2017) A Canine Model of Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 23:420-427
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
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

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