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: W A Erik Marijt, Mirjam H M Heemskerk, Freke M Kloosterboer, Els Goulmy, Michel G D Kester, Menno A W G van der Hoorn, Simone A P van Luxemburg-Heys, Manja Hoogeboom, Tuna Mutis, Jan Wouter Drijfhout, Jon J van Rood, Roel Willemze, J H Frederik Falkenburg
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 5 Pg. 2742-7 (Mar 04 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12601144 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD8 Antigens
• Chromium Radioisotopes
• Genetic Markers
• HA-1 antigen
• HA-2 antigen
• Minor Histocompatibility Antigens
• Neoplasm Proteins
• Oligopeptides
• Peptides
• Fusion Proteins, bcr-abl

Topics

• 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