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  • Review Article
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Molecules and mechanisms of the graft-versus-leukaemia effect

Nature Reviews Cancer volume 4, pages 371–380 (2004)Cite this article

Key Points

  • Allogeneic stem-cell transplantation, in which donor immune cells transplanted with bone-marrow stem cells recognize and eliminate leukaemia, is now recognized as an immunological modality for cancer therapy.

  • New approaches to transplantation take advantage of the allogeneic graft-versus-leukaemia (GVL) effect and facilitate the eradication of malignancies with low and minimally toxic doses of chemotherapy.

  • In human leukocyte antigen (HLA)-matched transplant recipients, T-cell responses to minor histocompatibility antigens are responsible for antileukaemic activity, but also cause graft-versus-host disease (GVHD). The discovery of the polymorphic genes that encode minor histocompability antigens is now proceeding rapidly and has identified a subset of these antigens that can be targeted for selective destruction of leukaemic cells without GVHD.

  • Non-polymorphic self-proteins are often overexpressed in leukaemic cells as a consequence of molecular dysregulation. Many of these proteins are expressed at low levels on a limited subset of normal cells, and T cells of sufficient avidity to distinguish malignant cells from normal cells can be identified and might also contribute to GVL activity.

  • The development of effective methods for isolating and propagating antigen-specific T cells indicates that adoptive T-cell therapy using T cells that are selected for recognition of leukaemic cells will be a useful adjunct to stem-cell transplantation for treating or preventing leukaemic relapse.

  • Approaches to regulate the fate and migration of adoptively transferred T cells are being developed and promise to improve the safety and efficacy of T-cell therapy for leukaemia.

Abstract

The ability of allogeneic bone-marrow cells and peripheral-blood stem cells to cure leukaemia remains the most striking example of the ability of the human immune system to recognize and destroy tumours. However, harnessing this 'graft-versus-leukaemia' effect to improve outcome for patients with advanced disease and segregating it from graft-versus-host disease have proven to be key challenges. The recent identification of molecules that are specifically expressed by leukaemic cells and that can be recognized by T cells has indicated that immunological reactivity can be targeted. This anticancer specificity of T cells should soon be routinely incorporated into allogeneic stem-cell transplant regimens to promote tumour eradication.

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Figure 1: Separating the graft-versus-leukaemia effect from graft-versus-host disease.
Figure 2: Adoptive immunotherapy with donor T cells to augment the graft-versus-leukaemia response.

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Acknowledgements

Work in the authors' laboratory is supported in part by grants from the National Institutes of Health and the Leukemia and Lymphoma Society. We thank past and present members of the Programme in Immunology for helpful discussions, and W. Hilliker for assistance in preparation of the manuscript.

Correction: The DOI number given for this article in the May 2004 print issue of Nature Reviews Cancer was wrong. The correct DOI number is: doi:10.1038/nrc1365.

Author information

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue, Seattle, 98109, Washington, USA

    Marie Bleakley & Stanley R. Riddell

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  1. Marie Bleakley
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  2. Stanley R. Riddell
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Correspondence to Stanley R. Riddell.

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DATABASES

Cancer.gov

acute lymphoblastic leukaemia

acute myelogenous leukaemia

chronic lymphoblastic leukaemia

chronic myelogenous leukaemia

melanoma

multiple myeloma

renal-cell carcinoma

LocusLink

BCL2A1

CD34

CLA1

CXCR4

HA-1

HA-2

HA-8

HB-1

IFN-γ

proteinase 3

SDF1

SMCY

UGT2B17

UTY

WT1

FURTHER INFORMATION

International Bone Marrow Transplant Registry

International Histocompatibility Working Group

Glossary

HLA MISMATCHED

Individuals mismatched (that is, non-identical) at one or more alleles of the human leukocyte antigen (hla) complex.

SYNGENEIC STEM-CELL TRANSPLANTATION

Stem-cell transplantation performed between genetically identical twins.

NON-MYELOABLATIVE CONDITIONING

Chemotherapy and/or low-dose irradiation given to prepare a patient for a haematopoietic stem-cell graft from another individual. The purpose is to immunosuppress the recipient, but the dose of chemoradiotherapy is not sufficient to irreversibly damage the patient's own bone marrow.

PANCYTOPAENIA

The severe reduction in the number of red blood cells, white blood cells and platelets that is seen after intensive chemotherapy.

HAPLO-IDENTICAL STEM-CELL TRANSPLANTATION

Stem-cell transplantation performed between individuals who are genetically identical for half of the human leukocyte antigen molecules.

BONE-MARROW CHIMAERA

These occur after allogeneic haematopoietic-stem-cell transplantation. In chimaeras, the bone marrow and haematopoietic cells are derived from the donor (one genotype), whereas the remaining cells in the body are all derived from the host (a second genotype).

SELF-TOLERANCE

The normal lack of an immunological response to autologous or self-antigens. A breakdown of self-tolerance can result in autoimmunity.

CD34+ CELLS

The CD34+ glycoprotein is a cell-surface marker of early haematopoietic progenitor cells.

WEGENER'S GRANULOMATOSIS

A rare disorder that is characterized by chronic inflammation of blood vessels and granulomas in the nasal passages, lungs and kidneys. This disorder is associated with antibodies directed against the proteinase enzyme of neutrophils.

CD4+ HELPER T-CELL RESPONSE

The subset of peripheral T cells that express the CD4 glycoprotein on the cell surface are called helper T cells. Helper T cells recognize peptide antigens presented on the cell surface in association with major histocompatibility complex class II molecules, and secrete cytokines that orchestrate responses by other immune cells, including CD8+ T cells and B cells.

CD28 CO-STIMULATION

T cells require several signals for full activation. Engagement of the t-cell receptor by human-leukocyte-antigen–peptide complexes provides a first signal that is required, but not sufficient, for T-cell activation. A second signal, or co-stimulation, is provided by engagement of other molecules, including CD28, which binds to CD80 (B7.1) and CD86 (B7.2) on antigen-presenting cells.

LYMPHOPAENIC

A state of having a subnormal level of circulating lymphocytes.

HOMEOSTATIC REGULATION

The tendency to correct abnormal levels of cells or molecules by feedback regulation. For example, in response to lymphopaenia, homeostatic mechanisms drive the expansion of residual lymphocytes to restore lymphocyte numbers to normal levels.

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Bleakley, M., Riddell, S. Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer 4, 371–380 (2004). https://doi.org/10.1038/nrc1365

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