title: Anti-CD45 radioimmunotherapy without TBI before transplantation facilitates persistent haploidentical donor engraftment.
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 μCi (90)Y-anti-CD45 antibody (30F11), with or without fludarabine (5 days starting day -8), with cyclophosphamide (CY; days -2 and +2) for graft-versus-host disease prophylaxis, and 1.5 × 10(7) haploidentical donor bone marrow cells (day 0). Haploidentical bone marrow transplantation (BMT) with 300 μCi (90)Y-anti-CD45 RIT and CY, without TBI or fludarabine, led to mixed chimeras with 81.3 ± 10.6% mean donor origin CD8(+) cells detected 1 month after BMT, and remained stable (85.5 ± 11% mean donor origin CD8(+) cells) 6 months after haploidentical BMT. High chimerism levels were induced across multiple hematopoietic lineages 28 days after haploidentical BMT with 69.3 ± 14.1%, 75.6 ± 20.2%, and 88.5 ± 11.8% CD3(+) T cells, B220(+) B cells, and CD11b(+) myeloid cells, respectively. Fifty percent of SJL leukemia-bearing mice treated with 400 μCi (90)Y-DOTA-30F11, CY, and haploidentical BMT were cured and lived >200 days. Mice treated with 200 μCi (90)Y-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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Hematology Division, Department of Medicine, University of Washington School of Medicine, Seattle, WA;
authors.forename: Johnnie J
authors.initials: JJ
authors.lastname: Orozco
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Aimee
authors.initials: A
authors.lastname: Kenoyer
authors.affiliation: Radiation Oncology, University of Washington, Seattle, WA;
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Balkin
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Ted A
authors.initials: TA
authors.lastname: Gooley
authors.affiliation: Radiation Oncology, University of Washington, Seattle, WA;
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.affiliation: Radiation Oncology, University of Washington, Seattle, WA;
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hylarides
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Sofia H L
authors.initials: SH
authors.lastname: Frost
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: Raya
authors.initials: R
authors.lastname: Mawad
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;
authors.forename: Paul
authors.initials: P
authors.lastname: O'Donnell
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Sandmaier
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Ephraim J
authors.initials: EJ
authors.lastname: Fuchs
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA; and.
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000954:Antigens, Surface / Q000378:metabolism; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D004195:Disease Models, Animal; D005260:Female; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics* / Q000276:immunology* / Q000528:radiation effects; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D064532:Histocompatibility Antigen H-2D / Q000235:genetics / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage*; D016130:Immunophenotyping; D007938:Leukemia / Q000401:mortality / Q000628:therapy; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D016499:Radioimmunotherapy / Q000379:methods; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D064532:Histocompatibility Antigen H-2D; D018796:Immunoconjugates; D017493:Leukocyte Common Antigens