Genomes and Genes
Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot
Principal Investigator: John M Pagel
Abstract: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) currently kill the majority of afflicted patients despite treatment with combination chemotherapy and hematopoietic cell transplantation (HCT). The option of HCT for potential therapy of acute leukemias must be further extended to patients who do not have a readily available HLA-matched donor, such as patients in ethnic minority groups. Radiolabeled anti-CD45 monoclonal antibodies (Ab) have been shown to improve outcomes for AML and MDS in the setting of HCT, but toxicity remains high and cure rates are suboptimal. The objective of this research proposal is to develop a strategy to improve the cure rate of AML and MDS using radioimmunotherapy (RIT) pretargeted to the CD45 cell antigen. In Aim 1 we will optimize the therapeutic efficacy and toxicities of the pretargeted RIT approach by comparing the relative merits of 90Y- and 177Lu-labeled biotin in comparative biodistribution, dosimetry and therapy experiments to determine if the shorter path length b emissions of 177Lu afford more favorable tumor-to-normal organ ratios than those achievable with 90Y. In Aim 2 we will assess the relative merits of HCT employing MHC-haploidentical stem cells utilizing myeloablative pretargeted RIT with an anti-CD45 Ab (30F11)-streptavidin (SA) conjugate followed by either 90Y- or 177Lu-labeled DOTA-biotin (as determined from aim 1 the best radionuclide will be used), compared to conventional RIT using a directly radiolabeled anti-CD45 Ab (30F11) in clinically relevant disseminated AML murine leukemia model in which both leukemic cells and normal hematopoietic cells express CD45. We anticipate that the results from this aim will demonstrate that pretargeted RIT is superior to conventional RIT and will allow us to improve the therapeutic efficacy of haploidentical BMT, with tolerable toxicity. In Aim 3 we will characterize and maximize the myelosuppressive and immunosuppressive effects of radiation delivered to lymphohematopoietic tissues via either 90Y- or 177Lu-labeled biotin (as determined from aim 1) in combination with optimized supplemental doses of total body irradiation (TBI) and Fludarabine (FLU) in a preclinical murine haploidentical HCT model employing cyclophosphamide (CY) post-transplant graft-vs-host disease prophylaxis. Reducing the TBI and FLU doses, while administering high doses of pretargeted 90Y- or 177Lu-biotin as part of a preparative regimen for marrow HCT, would depend upon the demonstration of the ability of such an approach to: 1) ablate the marrow space, and 2) produce adequate immunosuppression. Thus, in aim 3 we will also evaluate the kinetics and durability of hematopoietic and immune cell reconstitution using an anti-mCD45 Ab-SA conjugate (30F11 Ab-SA) and radiobiotin, followed by reduced doses of TBI and/or FLU and infusion of MHC-haploidentical BM and post-transplantation CY in a murine leukemia model. We hypothesize that the pretargeted RIT strategy defined in this proposal will amplify the amount of radiation delivered to leukemia cells, decrease the radiation delivered to the liver, lungs, and other normal organs, improve remission and cure rates, prolong survival, and markedly attenuate toxicities compared to conventional RIT combined with standard conditioning reagents. We therefore anticipate rapid translation of the optimized promising pretargeted RIT into our clinical RIT HCT program for AML and MDS.
Funding Period: 2013-08-01 - 2014-12-31
more information: NIH RePORT
- Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemiaRoland B Walter
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
J Clin Oncol 29:1190-7. 2011..Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD)...
- Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft modelJohn M Pagel
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Blood 118:703-11. 2011..These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia...
- Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemiaPamela S Becker
Division of Hematology and Medical Oncology, University of Washington, Seattle, WA 98109, USA
Br J Haematol 155:182-9. 2011..GCLAC is highly active in relapsed and refractory AML and warrants prospective comparison to other regimens, as well as study in untreated patients...
- Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphomaSteven I Park
Department of Medicine, University of North Carolina, Chapel Hill, USA
Clin Cancer Res 17:7373-82. 2011..We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem...
- Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDSH Joachim Deeg
Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 1024, USA
Blood 120:1398-408. 2012..Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics...
- Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia modelJohnnie J Orozco
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Blood 121:3759-67. 2013..7 K/µL 2 weeks after HSCT and recovery by 4 weeks. These data suggest that (211)At-anti-CD45 RIT in conjunction with HSCT may be a promising therapeutic option for AML...
- Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remissionRaya Mawad
Raya Mawad, Ted A Gooley, Vicky Sandhu, Bart Scott, Brenda M Sandmaier, Paul O Donnell, Pamela S Becker, Stephen Petersdorf, Kathleen Shannon Dorcy, Paul Hendrie, Mohamed L Sorror, Roland B Walter, H Joachim Deeg, Frederick R Appelbaum, Elihu H Estey, and John M Pagel, Fred Hutchinson Cancer Research Center Raya Mawad, Bart Scott, Brenda M Sandmaier, Paul O Donnell, Pamela S Becker, Stephen Petersdorf, Paul Hendrie, Mohamed L Sorror, Roland B Walter, H Joachim Deeg, Frederick R Appelbaum, Elihu H Estey, and John M Pagel, University of Washington, Seattle, WA and Jack Lionberger, Department of Preventive Dentistry
J Clin Oncol 31:3883-8. 2013..To determine the frequency of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1)...
- Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical designJack M Lionberger
Saint Louis University, Saint Louis, MO, USA
Br J Haematol 166:375-81. 2014....
- Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndromeRaya Mawad
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington Department of Medicine, University of Washington, Seattle, Washington
Biol Blood Marrow Transplant 20:1363-8. 2014..Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse. ..
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- Alpha Radioimmunotherapy for Lymphoma TreatmentBRENDA MARIE SANDMAIER; Fiscal Year: 2013..We anticipate that the information from these studies will allow rapid translation of the optimized promising RIT strategy using 211At-anti-CD45 MAb into our clinical RIT HCT program for NHL. ..
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