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 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 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.
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.
|Green, Damian J; O'Steen, Shyril; Lin, Yukang et al. (2018) CD38-bispecific antibody pretargeted radioimmunotherapy for multiple myeloma and other B-cell malignancies. Blood 131:611-620|
|Budde, Lihua E; Wu, David; Martin, Daniel B et al. (2018) Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial. Br J Haematol 183:601-607|
|Greenbaum, Adam M; Green, Damian J; Holmberg, Leona A et al. (2018) Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Blood Res 53:223-226|
|Green, Damian J; Press, Oliver W (2017) Whither Radioimmunotherapy: To Be or Not To Be? Cancer Res 77:2191-2196|
|O'Steen, Shyril; Green, Damian J; Gopal, Ajay K et al. (2017) Venetoclax Synergizes with Radiotherapy for Treatment of B-cell Lymphomas. Cancer Res 77:3885-3893|
|Cowan, Andrew J; Stevenson, Phillip A; Gooley, Ted A et al. (2017) Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma. Br J Haematol 176:583-590|
|Shadman, Mazyar; Gopal, Ajay K; Kammerer, Britt et al. (2016) Radioimmunotherapy consolidation using 131I-tositumomab for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma in first remission. Leuk Lymphoma 57:572-6|
|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|
|Graf, Solomon A; Gopal, Ajay K (2016) Idelalisib for the treatment of non-Hodgkin lymphoma. Expert Opin Pharmacother 17:265-74|
|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|
Showing the most recent 10 out of 133 publications