Glioma is the most common primary cancer of the central nervous system, and around 50% of patients present with the most aggressive form of the disease, glioblastoma. Conventional therapies, including surgery, radiotherapy, and pharmacotherapy (typically chemotherapy with temozolomide), have not resulted in major improvements in the survival outcomes of patients with glioblastoma. Reasons for this lack of progress include invasive tumour growth in an essential organ, which limits the utility of local therapy, as well as the protection of tumour cells by the blood–brain barrier, their intrinsic resistance to the induction of cell death, and lack of dependence on single, targetable oncogenic pathways, all of which impose challenges for systemic therapy. Furthermore, the unique immune environment of the central nervous system needs to be considered when pursuing immune-based therapeutic approaches for glioblastoma. Nevertheless, a range of different immunotherapies are currently being actively investigated in patients with this disease, spurred on by advances in immuno-oncology for other tumour types. Herein, we examine the current state of immunotherapy for gliomas, notably glioblastoma, the implications for combining the current standard-of-care treatment modalities with immunotherapies, potential biomarkers of response, and future directions for glioblastoma immuno-oncology.
The current standard of care for patients with glioblastoma includes surgery, temozolomide chemotherapy, radiotherapy, and corticosteroids, all of which have immunosuppressive effects; we must be cognizant of this complexity when developing immunotherapies.
Evidence for immunostimulatory effects of these treatments in the clinic, including abscopal effects, induction of immunogenic cell death, and depletion of regulatory T cells by temozolomide, remains limited.
Vaccination has been considered one of the most promising approaches to improving the outcomes of patients with glioblastoma, although negative results from several phase II and phase III trials challenge the current concept of vaccination as a single-modality immunotherapy.
Oncolytic viruses might exert pro-inflammatory responses that could potentially be exploited in future combined modality immunotherapy studies, whereas the future of chimeric antigen receptor (CAR) T cell therapy for glioblastoma depends on the identification of stably expressed and sufficiently tumour-specific antigens.
Immune-checkpoint inhibitors have promising therapeutic activity in preclinical glioblastoma models, whereas the results emerging from clinical trials in patients with recurrent glioblastoma are disappointing; larger studies are underway in the frontline treatment setting.
Future immune-based strategies are focused on combinations of different immune-checkpoint inhibitors with diverse treatment modalities that reverse local immunosuppression in the microenvironment, converting a ‘cold’ tumour into a ‘hot’ tumour.
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The authors thank A. Wu of the Johns Hopkins University School of Medicine for her help in formatting the manuscript.
M.L. has received research funding from Accuray, Agenus, Altor, Arbor, BMS, Celldex, and Immunocellular, and has been a consultant for Agenus, Baxter, BMS, Boston Biomedical, Oncorus, Regeneron, SQZ Biotechnologies, Stryker, and Tocagen. M.W. has received research grants from Acceleron, Actelion, Bayer, Merck (EMD), MSD, Novocure, OGD2, PIQUR, and Roche, and has received honoraria for lectures, advisory board participation, or consulting from AbbVie, BMS, Celldex, Merck (EMD), MSD, Novocure, Pfizer, Roche, Teva, and Tocagen. Y.X. and C.B. declare no competing interests.
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Lim, M., Xia, Y., Bettegowda, C. et al. Current state of immunotherapy for glioblastoma. Nat Rev Clin Oncol 15, 422–442 (2018). https://doi.org/10.1038/s41571-018-0003-5
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