title: Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation.
abstract: The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, CA, USA.
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Antonia
authors.initials: A
authors.lastname: Müller
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Goldstein
authors.forename: Evan
authors.initials: E
authors.lastname: Newell
authors.forename: Suparna
authors.initials: S
authors.lastname: Dutt
authors.forename: Debra
authors.initials: D
authors.lastname: Czerwinski
authors.forename: Robert
authors.initials: R
authors.lastname: Lowsky
authors.forename: Samuel
authors.initials: S
authors.lastname: Strober
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D007114:Immunization; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007942:Leukemia, Experimental / Q000276:immunology* / Q000628:therapy*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D022223:Vaccines, Subunit; D025721:WT1 Proteins