title: Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia.
abstract: Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been shown to be a successful treatment approach. The hematopoiesis-restricted minor histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of the recipient may serve as target antigens for alloreactive donor T cells. Recently we treated three mHAg HA-1- and/or HA-2-positive patients with a relapse of their disease after alloSCT with DLI from their mHAg HA-1- and/or HA-2-negative donors. Using HLA-A2HA-1 and HA-2 peptide tetrameric complexes we showed the emergence of HA-1- and HA-2-specific CD8(+) T cells in the blood of the recipients 5-7 weeks after DLI. The appearance of these tetramer-positive cells was followed immediately by a complete remission of the disease and restoration of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer-positive T cells isolated during the clinical response specifically recognized HA-1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited the growth of leukemic precursor cells in vitro. Thus, HA-1- and HA-2-specific cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate graft-versus-leukemia or myeloma reactivity resulting in a durable remission. This finding implies that in vitro generated HA-1- and HA-2-specific cytotoxic T lymphocytes could be used as adoptive immunotherapy to treat hematological malignancies relapsing after alloSCT.
authors.affiliation: Department of Hematology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. w.a.f.marijt@lumc.nl
authors.forename: W A Erik
authors.initials: WA
authors.lastname: Marijt
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.forename: Freke M
authors.initials: FM
authors.lastname: Kloosterboer
authors.forename: Els
authors.initials: E
authors.lastname: Goulmy
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Menno A W G
authors.initials: MA
authors.lastname: van der Hoorn
authors.forename: Simone A P
authors.initials: SA
authors.lastname: van Luxemburg-Heys
authors.forename: Manja
authors.initials: M
authors.lastname: Hoogeboom
authors.forename: Tuna
authors.initials: T
authors.lastname: Mutis
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Jon J
authors.initials: JJ
authors.lastname: van Rood
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002455:Cell Division; D002860:Chromium Radioisotopes; D041321:Chromosomes, Human, X; D041322:Chromosomes, Human, Y; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D005805:Genes, MHC Class I; D005819:Genetic Markers; D006410:Hematopoiesis; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D017404:In Situ Hybridization, Fluorescence; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000494:pharmacology*; D008957:Models, Genetic; D009363:Neoplasm Proteins / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D012008:Recurrence; D012074:Remission Induction; D033581:Stem Cell Transplantation; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D016827:CD8 Antigens; D002860:Chromium Radioisotopes; D005819:Genetic Markers; C110615:HA-1 antigen; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D009842:Oligopeptides; D010455:Peptides; D016044:Fusion Proteins, bcr-abl