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  • Review Article
  • Published:

Immunological off-target effects of imatinib

Nature Reviews Clinical Oncology volume 13, pages 431–446 (2016)Cite this article

Subjects

Key Points

  • Imatinib does not affect Philadelphia-chromosome-positive haematopoietic stem cells in patients achieving molecular response (MR); however, prolonged relapse-free survival can be achieved before treatment discontinuation, implying that efficient immunosurveillance has been established

  • In addition to targeting tumoural BCR–ABL1 and KIT oncogene products, imatinib modulates protein tyrosine kinases involved in key signalling pathways in both effector and regulatory immune cells implicated in cancer immunosurveillance

  • Low-dose imatinib has stimulatory effects on haematopoiesis and can contribute to immune-mediated clearance of pathogens

  • In patients with chronic myeloid leukaemia, imatinib elicits antigen-specific T-cell responses that can protect against relapses in patients with cytogenetically controlled or minimal disease

  • Imatinib boosts natural killer-cell-induced IFNα secretion and decreases regulatory T-cell numbers in patients with gastrointestinal tumours; NKp30 isoform patterns dictate the prognosis of the disease

  • We propose that novel treatment regimens combining imatinib with immunotherapies will enable long-term relapse-free survival to be achieved in a larger number of patients and will prevent the emergence of imatinib-resistant clones

Abstract

Around 15 years ago, imatinib mesylate (Gleevec® or Glivec®, Novartis, Switzerland) became the very first 'targeted' anticancer drug to be clinically approved. This drug constitutes the quintessential example of a successful precision medicine that has truly changed the fate of patients with Philadelphia-chromosome-positive chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours by targeting the oncogenic drivers of these diseases, BCR–ABL1 and KIT and/or PDGFR, mutations in which lead to gain of function of tyrosine kinase activities. Nonetheless, the aforementioned paradigm might not fully explain the clinical success of this agent in these diseases. Growing evidence indicates that the immune system has a major role both in determining the therapeutic efficacy of imatinib (and other targeted agents) and in restraining the emergence of escape mutations. In this Review, we re-evaluate the therapeutic utility of imatinib in the context of the anticancer immunosurveillance system, and we discuss how this concept might inform on novel combination regimens that include imatinib with immunotherapies.

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Figure 1: Key time points in the discovery and development of imatinib for the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST).
Figure 2: Effects of imatinib on components of the anticancer immunosurveillance system.
Figure 3: Natural and imatinib-induced immunosurveillance in gastrointestinal tumours (GISTs).
Figure 4: Combination immunotherapeutic approaches with imatinib.

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Acknowledgements

L.Z. and G.K. are supported by the Institut National Du Cancer (INCA), the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). L.Z. is also supported by the Swiss Institute for Experimental Cancer Research (ISREC) and the Swiss Bridge Foundation. MA is supported by the Cancer Research Institute (CRI) and the Ludwig Institute for Cancer Research (LICR).

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Authors and Affiliations

  1. Gustave Roussy Cancer Campus (GRCC), INSERM U1015, 114 rue Edouard Vaillant, Villejuif, 94805, France

    Laurence Zitvogel, Sylvie Rusakiewicz, Bertrand Routy & Maha Ayyoub

  2. Center of Clinical Investigations in Biotherapies of Cancer, CICBT1428, GRCC, Villejuif, 94805, France

    Laurence Zitvogel, Sylvie Rusakiewicz, Bertrand Routy & Maha Ayyoub

  3. Equipe 11 labelisée par la Ligue Nationale contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, University of Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France

    Guido Kroemer

  4. Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, 75015, France

    Guido Kroemer

  5. Metabolomics and Cell Biology Platforms, GRCC, Villejuif, 94805, France

    Guido Kroemer

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  1. Laurence Zitvogel
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All authors contributed to researching the data for the article and to discussion of the content. L.Z., M.A. and G.K. contributed to the writing of the article, and all authors reviewed and/or edited the manuscript before submission.

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Zitvogel, L., Rusakiewicz, S., Routy, B. et al. Immunological off-target effects of imatinib. Nat Rev Clin Oncol 13, 431–446 (2016). https://doi.org/10.1038/nrclinonc.2016.41

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