? Project 3 The majority of patients with multiple myeloma (MM) ultimately die of progressive disease despite high rates of initial response to novel agents. Recent advances allow patients with standard-risk MM to anticipate a median survival of over 7 years from diagnosis, however those with high-risk disease features continue to experience early relapse and death. Although autologous hematopoietic cell transplant (HCT) remains a standard of care, this intervention does not ameliorate the differences in outcome predicted by pre-HCT risk features. In contrast, responses observed after allogeneic HCT cannot be predetermined by high-risk features. Myeloablative conditioning regimens, in concert with a graft-versus-myeloma effect, have cured some patients with MM, but the accompanying toxicity and high rates of non-relapse mortality (NRM) have limited wide adoption. To minimize the risk of NRM associated with high-intensity preparative regimens, reduced-intensity conditioning (RIC) regimens have been introduced. Relapse after RIC however, remains the leading cause of death, and measures that can safely improve the efficacy of the conditioning regimen should be explored. The radio-sensitivity of malignant plasma cells has been well documented, and the poor prognosis associated with high-risk marrow cytogenetics is not predictive of response to radiation therapy. CD38 antigen-targeting with ?-emitter radioimmunotherapy (RIT) can eliminate disease in pre-clinical MM models. Based on the physical characteristics of ?-emitting radionuclides and new opportunities to harness their potential, there is a compelling rationale for employing ?-emitter RIT to treat MM. The ?-emitter astatine-211 ( 211At) deposits a very large amount of energy (~100 keV/?m) within a few cell diameters (50-90 ?m) resulting in irreparable double strand DNA breaks that overwhelm cellular repair mechanisms. The purpose of this application is to integrate ?-emitter RIT targeting CD38 (211At-OKT10-B10) into allogeneic HCT conditioning to improve outcomes without increasing toxicity and NRM. The project will address three hypotheses: 1). 211At-OKT10-B10 will be safe and well tolerated when integrated into an allogeneic HCT conditioning regimen 2). 211At-OKT10-B10 will selectively target all malignant plasma cells irrespective of mutational status, 3). B cell maturation antigen (BCMA) targeting with 211At-BCMA-B10 will represent a further refinement to targeting that will demonstrate efficacy in preclinical mouse models.

Public Health Relevance

? Project 3 Although donor stem cell transplant is the only treatment capable of curing multiple myeloma, it is too toxic, and attempts to reduce side effects have increased the likelihood of the cancer returning. This project is focused on developing a way to safely improve the effectiveness of donor stem cell transplant by coupling radiation to antibodies that directly target the cancer cells. In addition, we will explore measures that may make the treatment even more specific and less toxic.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA078902-22
Application #
10025201
Study Section
Special Emphasis Panel (ZCA1)
Project Start
1999-04-12
Project End
2025-06-30
Budget Start
2020-09-10
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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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
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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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