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  • Review Article
  • Published:

Antibody–drug conjugates in glioblastoma therapy: the right drugs to the right cells

Nature Reviews Clinical Oncology volume 14, pages 695–707 (2017)Cite this article

Subjects

Key Points

  • Cell-surface antigens expressed on glioblastoma cells that have proven resistant to signalling inhibition approaches — whether by tyrosine-kinase inhibitors or naked monoclonal antibodies — are attractive targets for antibody–drug conjugate (ADC) therapeutics

  • New-generation ADCs, exemplified by the newly developed tumour-selective anti-EGFR ADCs, are tolerable and have shown encouraging efficacy in early phase clinical trials

  • Emerging data from contemporary trials of ADCs can improve our understanding of the blood–brain barrier as a therapeutic hurdle in the treatment of patients with glioblastoma

  • Maximising the therapeutic potential of ADC-based therapies will require a paradigm shift in the approaches to investigating drug resistance, biomarker development, and functional imaging

  • ADCs can be used as monotherapies and, in addition, their limited toxicity profile can enable development of combinatorial approaches in rationally designed regimens to further enhance the therapeutic benefit of these agents

Abstract

Glioblastomas are high-grade brain tumours with a poor prognosis and, currently, few available therapeutic options. This lack of effective treatments has been linked to diverse factors, including target selection, tumour heterogeneity and poor penetrance of therapeutic agents through the blood–brain barrier and into tumours. Therapies using monoclonal antibodies, alone or linked to cytotoxic payloads, have proved beneficial for patients with different solid tumours; these approaches are currently being explored in patients with glioblastoma. In this Review, we summarise clinical data regarding antibody–drug conjugates (ADCs) against a variety of targets in glioblastoma, and compare the efficacy and toxicity of targeting EGFR with ADCs versus naked antibodies in order to illustrate key aspects of the use of ADCs in this malignancy. Finally, we discuss the complex challenges related to the biology and mutational changes of glioblastoma that can affect the use of ADC-based therapies in patients with this disease, and highlight potential strategies to improve efficacy.

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Figure 1: Effect of administration routes on uptake of antibody–drug therapies and other drugs.
Figure 2: Antibody–drug conjugate therapies and their mechanisms of action.
Figure 3: Intracranial targeting of high-grade gliomas by the tumour-specific ABT-806, the parental antibody of ABT-414.

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Acknowledgements

The authors were supported by the Cure Brain Cancer Foundation, the Operational Infrastructure Support Program, funding provided by the Victorian Government, the NHMRC Project Grant 1087580 and the NHMRC Program grant 1092788. H.K.G. is a recipient of a VCA Clinical Research Fellowship. A.M.S. is a recipient of an NHMRC Senior Practitioner Fellowship

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Authors and Affiliations

  1. Austin Health and Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, 3084, Victoria, Australia

    Hui K. Gan & Andrew M. Scott

  2. La Trobe University School of Cancer Medicine, 145 Studley Road, Heidelberg, 3084, Victoria, Australia

    Hui K. Gan & Andrew M. Scott

  3. Department of Medicine, University of Melbourne, 145 Studley Road, Heidelberg, 3084, Victoria, Australia

    Hui K. Gan & Andrew M. Scott

  4. Brain Tumour Centre, Erasmus MC Cancer Institute, Groene Hilledijk 301, 3075 EA, Rotterdam, Netherlands

    Martin van den Bent

  5. Department of Neurology & Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 161 Fort Washington Avenue, New York, 10032, New York, USA

    Andrew B. Lassman

  6. Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 2134, Boston, 02215, Massachusetts, USA

    David A. Reardon

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H.K.G. and A.M.S. wrote the manuscript. H.K.G., M.vD.B., D.A.R. edited the manuscript, and all authors reviewed the manuscript before submission.

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Correspondence to Hui K. Gan.

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Competing interests

H.K.G. is conducting an investigator-initiated study with AbbVie; has received travel support and research funding from AbbVie and Ignyta; honoraria from AbbVie, BMS, Merck Serono and Pfizer; and is affiliated with the Ludwig Institute for Cancer Research (New York, New York, USA). M.vD.B. has received honoraria from AbbVie, Actelion, Blue Earth Diagnostics, BMS, Cavion, Celldex, Merck, Novocure and Roche; and research funding from AbbVie and Roche. A.B.L. has received honoraria from Bioclinica, Cortice Biosciences, Genentech, Oxigene, prIME Oncology, Sapience Therapeutics and VBI Vaccines. D.A.R. has received honoraria from and has a consulting or advisory role with AbbVie, Amgen, BMS, Cavion, Celldex, Genentech, Inovio, Juno Pharmaceuticals, Merck, Novartis, Novocure, Oxigene, Regeneron, Roche and Stemline Therapeutics; is involved in speakers' bureaus with Merck and Roche; and has received research funding from Celldex, Incyte and Midatech. A.M.S. owns stock in and has an advisory role with Life Science Pharmaceuticals; received research funding from AbbVie, Avipep and Daiichi Sankyo; has patents, royalties, or other intellectual property with Abbvie, Kalobios, Life Science Pharmaceuticals, and Ludwig Institute for Cancer Research.

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Gan, H., van den Bent, M., Lassman, A. et al. Antibody–drug conjugates in glioblastoma therapy: the right drugs to the right cells. Nat Rev Clin Oncol 14, 695–707 (2017). https://doi.org/10.1038/nrclinonc.2017.95

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