Immunotherapy in glioblastoma: emerging options in precision medicine

Hodges, Tiffany R.; Ferguson, Sherise D.; Heimberger, Amy B.

doi:10.2217/cns-2016-0009

Cited by 11 publications

(8 citation statements)

References 113 publications

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“…Another promising avenue of treatment is immunotherapy against glioblastomas [42]. Withaferin A is a steroid that has been shown to inhibit T cell-mediated immune response [43].…”

Section: Discussionmentioning

confidence: 99%

Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields

et al. 2017

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BACKGROUND Glioblastoma (GBM) is the most aggressive and lethal form of brain cancer. Standard therapies are non-specific and often of limited effectiveness; thus, efforts are underway to uncover novel, unorthodox therapies against GBM. In previous studies, we investigated Withaferin A, a steroidal lactone from Ayurvedic medicine that inhibits proliferation in cancers including GBM. Another novel approach, tumor treating fields (TTFields), is thought to disrupt mitotic spindle formation and stymie proliferation of actively dividing cells. We hypothesized that combining TTFields with Withaferin A would synergistically inhibit proliferation in glioblastoma. METHODS Human glioblastoma cells (GBM2, GBM39, U87-MG) and human breast adenocarcinoma cells (MDA-MB-231) were isolated from primary tumors. The glioma cell lines were genetically engineered to express firefly luciferase. Proliferative potential was assessed either by bioluminescence imaging or cell counting via hemocytometer. RESULTS TTFields (4 V/cm) significantly inhibited growth of the four cancer cell lines tested (n=3 experiments per time point, 4 measurements per sample, p<0.02 at least; 2-way ANOVA, control vs. treatment). The combination of Withaferin A (10–100 nM) with TTFields significantly inhibited the growth of the glioma cells to a degree beyond that of Withaferin A or TTFields alone. The interaction of the Withaferin A and TTFields on glioma cells was found to be synergistic in nature (p<0.01, n=3 experiments). These findings were validated by both bioluminescence and hemocytometric measurements. CONCLUSIONS The combination of Withaferin A with TTFields represents a novel approach to treat GBM in a manner that is likely better than either treatment alone and that is synergistic.

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“…Another promising avenue of treatment is immunotherapy against glioblastomas [42]. Withaferin A is a steroid that has been shown to inhibit T cell-mediated immune response [43].…”

Section: Discussionmentioning

confidence: 99%

Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields

et al. 2017

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“…At the same time, there has been a real surge in the number of publications related to this topic (from 15 in 1999 to 164 in 2017 according to pubmed). The reader is redirected toward the large number of excellent reviews on this topic (Calinescu et al, 2015 ; Binder et al, 2016 ; Desaia et al, 2016 ; Hodges et al, 2016 ; Kamran et al, 2016 ; Dunn-Pirio and Vlahovic, 2017 ; Farber et al, 2017 ; Lyon et al, 2017 ; McGranahan et al, 2017 ; Miyauchi and Tsirka, 2017 ; Sahebjam et al, 2017 ; Tivnan et al, 2017 ), providing details about current or past clinical trials (Binder et al, 2016 ), and the different modes of action of these treatments (Calinescu et al, 2015 ; Curry and Lim, 2015 ).…”

Section: The Different Gbm Treatments Commercialized or Under Developmentioning

confidence: 99%

Glioblastoma Treatments: An Account of Recent Industrial Developments

Alphandéry

2018

Front. Pharmacol.

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The different drugs and medical devices, which are commercialized or under industrial development for glioblastoma treatment, are reviewed. Their different modes of action are analyzed with a distinction being made between the effects of radiation, the targeting of specific parts of glioma cells, and immunotherapy. Most of them are still at a too early stage of development to firmly conclude about their efficacy. Optune, which triggers antitumor activity by blocking the mitosis of glioma cells under the application of an alternating electric field, seems to be the only recently developed therapy with some efficacy reported on a large number of GBM patients. The need for early GBM diagnosis is emphasized since it could enable the treatment of GBM tumors of small sizes, possibly easier to eradicate than larger tumors. Ways to improve clinical protocols by strengthening preclinical studies using of a broader range of different animal and tumor models are also underlined. Issues related with efficient drug delivery and crossing of blood brain barrier are discussed. Finally societal and economic aspects are described with a presentation of the orphan drug status that can accelerate the development of GBM therapies, patents protecting various GBM treatments, the different actors tackling GBM disease, the cost of GBM treatments, GBM market figures, and a financial analysis of the different companies involved in the development of GBM therapies.

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“…1,2 In other cancers immunotherapy is already revolutionizing therapeutic options, which has encouraged testing similar approaches in GBM. [3][4][5][6] Nevertheless, the absence of any clinical breakthrough to date indicates that better understanding of the particularities of human GBM in response to immunotherapy is needed. Unfortunately, to achieve this, human GBM cells cannot be used for most preclinical mechanistic studies of immunotherapy because of the obligation to use a fully immunocompetent animal model.…”

Section: Introductionmentioning

confidence: 99%

Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models

et al. 2018

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Immune checkpoint blockade (ICB) is currently evaluated in patients with glioblastoma (GBM), based on encouraging clinical data in other cancers, and results from studies with the methylcholanthrene-induced GL261 mouse glioma. In this paper, we describe a novel model faithfully recapitulating some key human GBM characteristics, including low mutational load, a factor reported as a prognostic indicator of ICB response. Consistent with this observation, SB28 is completely resistant to ICB, contrasting with treatment sensitivity of the more highly mutated GL261. Moreover, SB28 shows features of a poorly immunogenic tumor, with low MHC-I expression and modest CD8 + T-cell infiltration, suggesting that it may present similar challenges for immunotherapy as human GBM. Based on these key features for immune reactivity, SB28 may represent a treatment-resistant malignancy likely to mirror responses of many human tumors. We therefore propose that SB28 is a particularly suitable model for optimization of GBM immunotherapy.

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Immunotherapy in glioblastoma: emerging options in precision medicine

Cited by 11 publications

References 113 publications

Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields

Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields

Glioblastoma Treatments: An Account of Recent Industrial Developments

Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models

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