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The Role of Checkpoint Inhibitors in Glioblastoma

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Abstract

Given its poor prognosis, glioblastoma represents an area of high unmet clinical need. Standard of care for the treatment of glioblastoma in the frontline setting is limited to surgical resection, radiation, and temozolomide, with the more recent addition of Tumor Treating Fields. Several agents, including bevacizumab, lomustine, and carmustine have been approved in the recurrent setting. To date, no therapies have demonstrated substantial survival benefit beyond standard of care. An expanding understanding of the role of the immune system in fighting cancer has led to the development and approval of various immunotherapeutic approaches across solid tumors. In glioblastoma, the notion of a highly immune-restricted central nervous system has also evolved, further providing the rationale for testing therapies that promote immune trafficking to the CNS and infiltration into the tumor to counteract the immunosuppressive mechanisms that support tumor progression. There are five broad categories of immunotherapies currently being tested in GBM: vaccines, cytokine therapy, oncolytic viral therapy, chimeric antigen receptor T cell therapy, and checkpoint inhibitors. This review focuses on checkpoint inhibitors in GBM, the rationale for its use, preclinical data, and early clinical experience. Efficacy data are limited, and while a number of late-stage trials are ongoing, early trials showed no benefit in survival. There is a dizzying array of combinations being tested in clinical studies with an urgent need for a rational approach to determine the role of checkpoint inhibitors in glioblastoma, including the optimal combinations, and identification of biomarkers or predictive models to determine which patients may benefit from immunotherapy.

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Authors and Affiliations

  1. Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, NA10, Cleveland, OH, 44195, USA

    Kunal Desai & Anne Hubben

  2. Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Manmeet Ahluwalia

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  1. Kunal Desai
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Correspondence to Kunal Desai.

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Dr. Kunal Desai and Dr. Anne Hubben declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Dr. Ahluwalia has received consulting fees or honorarium from Prime Education, Prime Oncology, Elsevier, Monteris AstraZeneca, Bristol-Myers Squibb, Abbvie, CBT Pharmaceuticals, Kadmon, VBI Vaccines, Flatiron Health, Varian Medical Systems, Karyopharm Therapeutics. Dr. Ahluwalia has stock/stock options in Mimivax and Doctible. Dr. Ahluwalia has grants received or pending from Novartis, Novocure, Astrazeneca, Abbvie, BMS, Pharamacyclics, Incyte, Merck, Bayer, Mimivax, and Boston Biomedical.

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Desai, K., Hubben, A. & Ahluwalia, M. The Role of Checkpoint Inhibitors in Glioblastoma. Targ Oncol 14, 375–394 (2019). https://doi.org/10.1007/s11523-019-00655-3

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