Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment

Johnnie J. Orozco, Aimee Kenoyer, Ethan R. Balkin, Ted A. Gooley, Donald K. Hamlin, D. Scott Wilbur, Mark D. Hylarides, Sofia H.L. Frost, Raya Mawad, Paul O'Donnell, Brenda M. Sandmaier, Ephraim J. Fuchs, Leo Luznik, Damian J. Green, Ajay K. Gopal, Oliver W. Press, John M. Pagel

Research output: Contribution to journalArticle

Abstract

Many patients with hematologic malignancies cannot tolerate hematopoietic cell transplantation (HCT), whereas others may not have a compatible human leukocyte antigen- matched donor. To overcome these limitations, we optimized a conditioning regimen employing anti-CD45 radioimmunotherapy (RIT) replacing total body irradiation (TBI) before haploidentical HCT in a murine model. Mice received 200 to 400 mCi 90Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and 12) for graft-versus-host disease prophylaxis, and 1.5 3 107 haploidentical donor bone marrow cells (day 0). Haploidentical bone marrow transplantation (BMT) with 300 mCi 90Y-anti-CD45 RIT and CY, without TBI or fludarabine, led to mixed chimeras with 81.3 6 10.6% mean donor origin CD81 cells detected 1 month after BMT, and remained stable (85.5611% mean donor origin CD81 cells) 6 months after haploidentical BMT. High chimerism levels were induced across multiple hematopoietic lineages 28 days after haploidentical BMT with 69.3 6 14.1%, 75.6 6 20.2%, and 88.5 6 11.8% CD31 T cells, B2201 B cells, and CD11b1 myeloid cells, respectively. Fifty percent of SJL leukemia-bearing mice treated with 400 mCi 90Y-DOTA-30F11, CY, and haploidentical BMT were cured and lived >200 days. Mice treated with 200 mCi 90Y-DOTA-30F11 had a median overall survival of 73 days, while untreated leukemic mice had a median overall survival of 34 days (P < .001, Mantel-Cox test). RIT-mediated haploidentical BMT without TBI may increase treatment options for aggressive hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)352-359
Number of pages8
JournalBlood
Volume127
Issue number3
DOIs
StatePublished - Jan 21 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Orozco, J. J., Kenoyer, A., Balkin, E. R., Gooley, T. A., Hamlin, D. K., Wilbur, D. S., Hylarides, M. D., Frost, S. H. L., Mawad, R., O'Donnell, P., Sandmaier, B. M., Fuchs, E. J., Luznik, L., Green, D. J., Gopal, A. K., Press, O. W., & Pagel, J. M. (2016). Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment. Blood, 127(3), 352-359. https://doi.org/10.1182/blood-2014-12-617019