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Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia

Leukemia volume 21, pages 53–60 (2007)Cite this article

Abstract

Advances in our understanding of the Toll-like receptors (TLRs) have led to the identification of several agonists that are suitable for clinical development. Chronic lymphocytic leukemia (CLL) may be especially amenable to TLR agonists because it is an immunologically susceptible tumor with strong expression of several TLRs, particularly TLR-7 and TLR-9. TLR agonists may indirectly clear CLL cells by enhancing the activity of natural killer and tumor-reactive T cells, or by altering the tumor microenvironment and inhibiting angiogenesis. However, signaling pathways can be activated directly in CLL cells by TLR-7 and TLR-9 agonists, leading to the production of cytokines and costimulatory molecules in a manner that is dependent on the underlying cytogenetic abnormalities, but rendering the tumor cells more sensitive to killing by cytotoxic T cells, immunotoxins and some chemotherapeutic drugs. Imidazoquinolines are TLR-7 agonists with strong local activity against CLL, and phase I trials of systemically administered imidazoquinolines (and also cytosine-phosphate-guanosine oligonucleotides that are TLR-9 agonists) are currently ongoing at different centers. The potential importance of these TLR agonists in the treatment of CLL is suggested by their ability to sensitize tumor cells to cytotoxic agents, and their future probably lies in combination with radiotherapies, chemotherapies, monoclonal antibodies and cancer vaccines.

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Acknowledgements

This work was supported by grants from the Ontario Cancer Research Network (OCRN) and the Canadian Institutes of Health Research (CIHR) to DS. This work is dedicated to the memory of Bernard Spaner.

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Authors and Affiliations

  1. Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto, Canada

    D E Spaner

  2. Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada

    D E Spaner

  3. Department of Medicine, University of Toronto, Toronto, Canada

    D E Spaner

  4. Department of Medical Biophysics, University of Toronto, Toronto, Canada

    D E Spaner

  5. Department of Pharmacology, 3M Pharmaceuticals, St Paul, MN, USA

    A Masellis

  6. Department of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

    A Masellis

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Correspondence to D E Spaner.

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Spaner, D., Masellis, A. Toll-like receptor agonists in the treatment of chronic lymphocytic leukemia. Leukemia 21, 53–60 (2007). https://doi.org/10.1038/sj.leu.2404456

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