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Experimental and clinical approaches for optimization of the graft-versus-leukemia effect

Nature Clinical Practice Oncology volume 4, pages 404–414 (2007)Cite this article

Abstract

The goal of allogeneic (allo)-hematopoietic stem-cell transplantation (HSCT) in the treatment of hematologic malignancies is to harness the graft-versus-leukemia (GVL) effect, while minimizing the risk of graft-versus-host disease (GVHD). Allo-HSCT research has focused on the GVL target antigens and effector mechanisms, and on potential approaches to exploit GVL independently of GVHD. Donor lymphocyte infusion (DLI) achieves the most powerful anti-leukemic responses, and this approach is often used in combination with nonmyeloablative transplant regimens to optimize GVL and reduce GVHD. Serial, dose-escalating, and CD8+ T-cell-depleted DLI have been introduced into clinical practice, while other variants of DLI have so far been explored only in animal models. The role of naturally occurring regulatory T cells in transplantation tolerance is being increasingly acknowledged, and murine studies indicate the potential ability of T cells to regulate GVHD while maintaining GVL. Experimental and clinical studies have demonstrated the importance of host-type chimerism, particularly for antigen-presenting cells, in determining the occurrence of DLI-induced GVL. Murine studies could assist in the development of clinical strategies targeted at antigen-presenting cells. Clinical studies exploiting natural killer-cell-mediated antitumor reactivity in the context of killer inhibitory receptor-ligand-mismatched allo-HSCT have provided promising results.

Key Points

  • Graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect are closely related immunologic phenomena that occur following allogeneic hematopoietic stem-cell transplantation; however, experimental and clinical data indicate that in selected circumstances the GVL effect can be dissociated from GVHD

  • Nonmyeloablative stem-cell transplantation allows donor engraftment and avoids procedure-related complications, thereby providing a platform for subsequent adoptive immunotherapy, an approach that has successfully broadened patient eligibility for stem-cell transplantation procedures to include older and weaker individuals

  • Minor histocompatibility complex antigens are the most important target antigens of T-cell-mediated GVL responses, and represent attractive targets for adoptive immunotherapy

  • Donor lymphocyte infusion can generate strong anti-leukemic responses and provide a platform for the development of more-refined approaches to the GVL effect, some of which are being applied in the clinic

  • Natural killer cells have been shown to mediate anti-leukemic reactivity in the context of killer inhibitory receptor-ligand-mismatched allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia, and for other hematologic malignancies

  • Other potentially interesting methods of using the GVL effect to treat leukemia, such as leukemia-specific T cells, selective depletion of potentially alloreactive T cells from donor lymphocyte infusions, suicide-gene-transduced effector T cells, expanded regulatory T cells, and dendritic-cell-based therapies, have proven effective experimentally, but have not yet entered clinical trials

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Acknowledgements

B Sprangers and B Van Wijmeersch are Doctoral Fellows, and AD Billiau is a Postdoctoral Fellow, of the Flanders Fund for Scientific Research, Belgium. S Fevery is a Doctoral Fellow financially supported by a grant from the Flanders Fund for Scientific Research.

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  1. B Sprangers,ws, M Waer is a Professor of Nephrology, and AD Billiau is a Postdoctoral Fellow, all in the Laboratory of Experimental Transplantation, University of Leuven, Leuven, Belgium.,

    Ben Sprangers, Bart Van Wijmeersch, Sabine Fevery, Mark Waer & An D Billiau

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Sprangers, B., Van Wijmeersch, B., Fevery, S. et al. Experimental and clinical approaches for optimization of the graft-versus-leukemia effect. Nat Rev Clin Oncol 4, 404–414 (2007). https://doi.org/10.1038/ncponc0848

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