Allogeneic hematopoietic cell transplantation (HCT) for treatment of hematological malignancies frequently fails because of disease recurrence. Attempts at intensifying the preparative regimen have been limited by associated toxicities due to the non-specific nature of most conditioning agents. The overall goal of Project 1 is to overcome this limitation by delivering targeted therapy to sites of leukemic involvement to decrease the risk of relapse after HCT without increased toxicity. We have shown that l-anti-CD45 antibody (Ab; BCS) can deliver targeted radiation to hematopoietic tissues, with 2-3 times more radiation delivered to marrow, up to 12 times more to spleen, and 2- 8 times more to lymph nodes than to liver, lung or kidney. This observation has been translated to human studies that demonstrated the feasibility of combining I- BC8 Ab with a reduced-intensity preparative regimen of fludarabine (FLU) and total body irradiation (TBI) in patients with advanced acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). We now propose three specific aims to extend these preliminary observations.
In Aim 1 we will perform a phase II study to define the efficacy of using l-BC8 Ab combined with FLU and TBI in older patients with AML in remission.
In Aim 2 we will extend this approach to patients lacking HLA-matched donors by determining the maximally tolerated dose (MTD) of radiation delivered by l-BC8 Ab that can be combined with a haplo-identical HCT strategy employing 2 Gy TBI, FLU, and cyclophosphamide. We will then conduct a phase II study of haplo-identical transplantation in order to estimate the efficacy of this regimen.
In Aim 3, we will build on our single-center experience by performing a multi-center phase I study to estimate the MTD of radiation that can be delivered via Y-BC8 Ab when combined with FLU and 2 Gy TBI as a preparative regimen for older patients with advanced myeloid malignancies, and to determine the feasibility of exporting such a regimen to other institutions. We anticipate that these studies will eventually allow us to carry out definitive Phase III studies in which allogeneic HCT approaches employing I- or Y-BC8 Ab are compared to standard reduced-intensity and haplo-identical HCT methods. We are optimistic that these interventions will enhance the prognosis for patients with acute leukemias and myelodysplasia by increasing the response and survival rates, while minimizing toxicities.
Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) currently kill the majority of affected patients despite treatment with chemotherapy and hematopoietic cell transplantation (HCT). In this project, we plan to target radiation therapy directly to the leukemia cells using a radiolabeled antibody for patients undergoing HCT with or without a matched donor (such as patients in ethnic minority groups). This could cure more patients and cause less toxicity than current therapies.
|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|
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