The objective of Project 3 (Pretargeted Radioimmunotherapy for Hematologic Malignancies) is to improve the efficacy and diminish the toxicity of radioimmunotherapy (RIT) by removing the proportion of radioisotope that fails to bind to tumor and remains in the blood perfusing normal organs. This goal will be achieved by employing a multi-step """"""""pretargeted"""""""" RIT (PRIT) approach in which conjugates of the anti-CD45 BCS Ab and streptavidin are injected first into patients with CD45-expressing hematologic malignancies followed by infusion of radiolabeled DOTA-biotin 48 hours later.
In Aim 1, we will conduct a phase I trial of non-myeloablative allogeneic hematopoietic cell transplantation (HCT) using PRIT with BCS-SA and radiobiotin followed by fludarabine (FLU) and 2 Gy total body irradiation (TBI) for relapsed or refractory acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or high risk myelodysplasia (MDS). The primary objective of this Aim is to estimate the maximum tolerated dose (MTD) of [90]Y-DOTA-biotin when given with this transplant conditioning regimen. Secondary objectives include defining the pharmacokinetics (PK) and biodistributions of the BCS-SA and radiolabeled-DOTA-biotin reagents and examining their potential efficacy.
In Aim 2, we will conduct a phase I trial of myeloablative autologous HCT for relapsed lymphoma using PRIT with BCS-SA and radiobiotin followed by etoposide (VP16) and cyclophosphamide (CY). The primary objective of this study is to estimate the MTD of [90]Y-DOTA-biotin using pre-targeting technology followed by autologous HCT in patients with relapsed lymphoma.
In Aim 3 we will compare and contrast the biodistributions and dosimetries of radiobiotin pretargeted using anti-CD45 BCS-SA with those observed with directly radiolabeled anti-CD45 BCS Ab in patients with leukemia and lymphoma. The overall goal of Project 1 is to improve the delivery of radiation to tumor cells compared to normal tissues, thereby allowing escalation of the tumor dose while maintaining well-defined, tolerable upper limits on the doses to critical normal organs. Successful execution of this Project should lead to improvements in the cure rates of patients with relapsed and refractory AML, ALL, MDS and NHL undergoing HCT.

Public Health Relevance

Fewer than 35% of patients with leukemia and lymphoma are currently cured. Chemoradiotherapy with hematopoietic cell transplantation is the best treatment for most patients but has high rates of morbidity, mortality, and relapse. Radiolabeled antibodies show promise;however, normal organs of the body also receive the radiation. We believe we can improve the ratios of radiation absorbed by tumor sites relative to normal organs with pretargeted radioimmunotherapy and increase the effectiveness of treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA044991-25
Application #
8546159
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
25
Fiscal Year
2013
Total Cost
$301,631
Indirect Cost
$117,325
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Cowan, Andrew J; Stevenson, Philip A; Cassaday, Ryan D et al. (2016) Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission. Biol Blood Marrow Transplant 22:380-5
Orozco, Johnnie J; Kenoyer, Aimee; Balkin, Ethan R et al. (2016) Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood 127:352-9
Rufener, Gregory A; Press, Oliver W; Olsen, Philip et al. (2016) Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab. Cancer Immunol Res 4:509-19
Chen, Robert; Gopal, Ajay K; Smith, Scott E et al. (2016) Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128:1562-6
Graf, Solomon A; Gopal, Ajay K (2016) Idelalisib for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 17:265-74
Green, D J; Bensinger, W I; Holmberg, L A et al. (2016) Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Bone Marrow Transplant 51:1330-1336
Cassaday, Ryan D; Stevenson, Philip A; Gooley, Theodore A et al. (2015) High-dose CD20-targeted radioimmunotherapy-based autologous transplantation improves outcomes for persistent mantle cell lymphoma. Br J Haematol 171:788-97
Cassaday, Ryan D; Storer, Barry E; Sorror, Mohamed L et al. (2015) Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation. Biol Blood Marrow Transplant 21:281-7
Graf, S A; Stevenson, P A; Holmberg, L A et al. (2015) Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma. Ann Oncol 26:2323-8
Frost, Sofia H L; Miller, Brian W; Bäck, Tom A et al. (2015) α-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After 211At-Radioimmunotherapy for Hematopoietic Cell Transplantation. J Nucl Med 56:1766-73

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