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PMID: 12601144 Published · ppublish English Case Reports Journal Article Research Support, Non-U.S. Gov't

Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 5 ·2003-03-04 ·Pages 2742-7

Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, Falkenburg JH

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.

MeSH Terms
Bone Marrow Cells/cytology CD8 Antigens/biosynthesis CD8-Positive T-Lymphocytes/metabolism Cell Division Chromium Radioisotopes Chromosomes, Human, X Chromosomes, Human, Y Female Fusion Proteins, bcr-abl/metabolism Genes, MHC Class I Genetic Markers Hematopoiesis Humans Immunotherapy/methods In Situ Hybridization, Fluorescence Leukemia/drug therapy,pathology Male Middle Aged Minor Histocompatibility Antigens/pharmacology Models, Genetic Neoplasm Proteins/pharmacology Oligopeptides/pharmacology Peptides/chemistry Phenotype Recurrence Remission Induction Stem Cell Transplantation Time Factors Transplantation, Homologous
Chemicals
CD8 Antigens Chromium Radioisotopes Genetic Markers HA-1 antigen HA-2 antigen Minor Histocompatibility Antigens Neoplasm Proteins Oligopeptides Peptides Fusion Proteins, bcr-abl
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Marijt W A Erik
Department of Hematology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. [email protected]
Heemskerk Mirjam H M
Kloosterboer Freke M
Goulmy Els
Kester Michel G D
van der Hoorn Menno A W G
van Luxemburg-Heys Simone A P
Hoogeboom Manja
Mutis Tuna
Drijfhout Jan Wouter
van Rood Jon J
Willemze Roel
Falkenburg J H Frederik
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0530192100
Email
[email protected]
Published
2003-03-04
Epub
2003-00-24
Pages
2742-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC151411
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0530192100 PMC Full Text View journal details
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