Bone Marrow Transplantation for Hematologic Malignancies using Novel Radioimmunot

Summary

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

Top Publications

  1. pmc Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia
    Roland B Walter
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    J Clin Oncol 29:1190-7. 2011
  2. pmc Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model
    John M Pagel
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Blood 118:703-11. 2011
  3. ncbi Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia
    Pamela S Becker
    Division of Hematology and Medical Oncology, University of Washington, Seattle, WA 98109, USA
    Br J Haematol 155:182-9. 2011
  4. pmc Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma
    Steven I Park
    Department of Medicine, University of North Carolina, Chapel Hill, USA
    Clin Cancer Res 17:7373-82. 2011
  5. pmc Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS
    H Joachim Deeg
    Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109 1024, USA
    Blood 120:1398-408. 2012
  6. pmc Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model
    Johnnie J Orozco
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Blood 121:3759-67. 2013
  7. pmc Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission
    Raya 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
  8. pmc Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design
    Jack M Lionberger
    Saint Louis University, Saint Louis, MO, USA
    Br J Haematol 166:375-81. 2014
  9. pmc Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome
    Raya 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

Research Grants

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
  2. Alpha Radioimmunotherapy for Lymphoma Treatment
    BRENDA MARIE SANDMAIER; Fiscal Year: 2013
  3. THERAPY OF LYMPHOMA/LEUKEMIA WITH MONOCLONAL ANTIBODIES
    Oliver W Press; Fiscal Year: 2013
  4. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
  5. Novel Approaches to Stem Cell Transplantation
    Nelson J Chao; Fiscal Year: 2013
  6. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
  7. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
  8. Herpesviral, Oncogenesis, Latency and Reactivation
    NANCY JOAN RAAB-TRAUB; Fiscal Year: 2013
  9. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
  10. CD45 Pretargeted Radioimmunotherapy for AML
    Oliver W Press; Fiscal Year: 2013

Detail Information

Publications9

  1. pmc Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia
    Roland 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)...
  2. pmc Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model
    John 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...
  3. ncbi Clofarabine with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming for relapsed and refractory acute myeloid leukaemia
    Pamela 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...
  4. pmc Pretargeted radioimmunotherapy using genetically engineered antibody-streptavidin fusion proteins for treatment of non-hodgkin lymphoma
    Steven 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...
  5. pmc Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS
    H 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...
  6. pmc Anti-CD45 radioimmunotherapy using (211)At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model
    Johnnie 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...
  7. pmc Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission
    Raya 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)...
  8. pmc Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design
    Jack M Lionberger
    Saint Louis University, Saint Louis, MO, USA
    Br J Haematol 166:375-81. 2014
    ....
  9. pmc Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome
    Raya 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. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Alpha Radioimmunotherapy for Lymphoma Treatment
    BRENDA 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. ..
  3. THERAPY OF LYMPHOMA/LEUKEMIA WITH MONOCLONAL ANTIBODIES
    Oliver W Press; Fiscal Year: 2013
    ..We anticipate that the investigations described in this application will allow us to maximize the therapeutic efficacy and minimize the toxicity of myeloablative RIT for hematologic malignancies. ..
  4. Risk-Based Breast Cancer Screening in Community Settings
    Diana L Miglioretti; Fiscal Year: 2013
    ..The program represents an integrated effort to improve screening with the overall aim of averting deaths from breast cancer while minimizing harms. ..
  5. Novel Approaches to Stem Cell Transplantation
    Nelson J Chao; Fiscal Year: 2013
    ..Our commitment to patients'welfare and improved outcomes continues to drive our efforts. The lessons learned from these studies will also be applicable to other forms of allogeneic hematopoietic cell transplantation. ..
  6. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
    ..D.) D. Animal Core (Director: J.N. Sarkaria, M.D.;Co-Director: I.F. Parney, M.D., Ph.D.) E. Clinical Research Core (Director: J.C. Buckner, M.D.;Co-Director: D. H. Lachance, M.D.) Developmental Research Portfolio ..
  7. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
    ..This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology. ..
  8. Herpesviral, Oncogenesis, Latency and Reactivation
    NANCY JOAN RAAB-TRAUB; Fiscal Year: 2013
    ..abstract_text> ..
  9. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  10. CD45 Pretargeted Radioimmunotherapy for AML
    Oliver W Press; Fiscal Year: 2013
    ....
  11. Bispecific Antibody Engineering for AML RIT
    Oliver W Press; Fiscal Year: 2013
    ..We anticipate rapid translation of the results of these preclinical experiments into our clinical RIT program for AML. ..
  12. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
    ..This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens. ..
  13. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  14. SPORE in GI Cancer
    Robert J Coffey; Fiscal Year: 2013
    ..Administrative Core B. Translational Pathology &Imaging Core C. Biostatistics &Bioinformatics Career Development Program Developmental Research Program ..
  15. Immuno/Immuno-Gene Therapies for Thoracic Malignancies
    STEVEN MARK ALBELDA; Fiscal Year: 2013
    ..Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer. ..
  16. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  17. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
    ..The CIRNA is proposed to replace the TTURC, since this NIH initiative is ending. ..
  18. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  19. T CELL MEMORY TO PATHOGENS: GENERATION AND FUNCTION
    Susan L Swain; Fiscal Year: 2013
    ..abstract_text> ..
  20. Radioimmunotherapy for Multiple Myeloma
    Damian J Green; Fiscal Year: 2013
    ..This project is designed to develop a new approach, already proven effective for patients with leukemia and lymphoma, that directly targets multiple myeloma cells with small radioactive particles to selectively destroy them. ..
  21. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  22. H. pylori-induced inflammation and gastric cancer
    Richard M Peek; Fiscal Year: 2013
    ..abstract_text> ..
  23. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
    ..We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection. ..
  24. Radiation Bystander Effects: Mechanisms
    Tom K Hei; Fiscal Year: 2013
    ..abstract_text> ..
  25. Infections and The Stability of Transplantation Tolerance
    Anita S Chong; Fiscal Year: 2013
    ..abstract_text> ..