Current Trends in Glioblastoma Multiforme Treatment: Radiation Therapy and Immune Checkpoint Inhibitors

Nicholas, Sarah E.; Mathios, Dimitris; Ruzevick, Jacob; Jackson, Christopher M.; Yang, Isaac; Lim, Michael

doi:10.14791/btrt.2013.1.1.2

Cited by 16 publications

(13 citation statements)

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“…In light of the potential synergisms, commencing checkpoint inhibitor treatment prior to radiotherapy would seem rational, however, clinical trials are needed to establish optimal combination strategies. 100 …”

Section: Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

Prospects of immune checkpoint modulators in the treatment of glioblastoma

et al. 2015

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Glioblastoma is the most common primary brain tumour in adults. Prognosis is poor: even with the current gold-standard first-line treatment—maximal safe resection and combination of radiotherapy with temozolomide chemotherapy—the median overall survival time is only approximately 15–17 months, because the tumour recurs in virtually all patients, and no commonly accepted standard treatment for recurrent disease exists. Several targeted agents have failed to improve patient outcomes in glioblastoma. Immunotherapy with immune checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab has provided relevant clinical improvements in other advanced tumours for which conventional therapies have had limited success, making immunotherapy an appealing strategy in glioblastoma. This Review summarizes current knowledge on immune checkpoint modulators and evaluates their potential role in glioblastoma on the basis of preclinical studies and emerging clinical data. Furthermore, we discuss challenges that need to be considered in the clinical development of drugs that target immune checkpoint pathways in glioblastoma, such as specific properties of the immune system in the CNS, issues with radiological response assessment, and potential interactions with established and emerging treatment strategies.

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Section: Checkpoint Inhibitors In Glioblastomamentioning

confidence: 99%

Prospects of immune checkpoint modulators in the treatment of glioblastoma

et al. 2015

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“…Radiation remains the main treatment approach for glioblastoma, and stereotactic radiosurgery has been implemented with great success in glioblastoma mouse models in our laboratory and in others as an immunostimulatory strategy . Using these models, it has also been demonstrated in a number of studies that the combination of SRS with immune checkpoint blockers has significant synergistic survival benefit in mice harboring glioblastoma tumors by increasing antigen presentation and promoting a proinflammatory tumor microenvironment . Therefore, it may be beneficial to combine SRS with other immunomodulators, such as IL‐15.…”

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confidence: 99%

“…[11][12][13] Using these models, it has also been demonstrated in a number of studies that the combination of SRS with immune checkpoint blockers has significant synergistic survival benefit in mice harboring glioblastoma tumors by increasing antigen presentation and promoting a proinflammatory tumor microenvironment. [11][12][13][14] Therefore, it may be beneficial to combine SRS with other immunomodulators, such as IL-15.…”

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Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model

et al. 2015

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Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereo-tactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.

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“…GBM is the deadliest of all brain cancers in adults and all patients ultimately succumb to the tumor. The standard-of-care involves surgical removal of the bulk tumor followed by radiotherapy and temozolomide treatment [1][2][3][4] . Reasons for treatment failure include the spread of tumor cells into the normal parenchyma, far beyond the detectable tumor, radio-and chemo-therapy resistance of the tumor cells and the intratumoral heterogeneity and plasticity of GBM [5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

Bhat

Ioannidis

et al. 2020

Preprint

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BackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation.MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells.ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.Key points- Combined treatment of ONC201 and radiation exhibit anti-tumor effects on cells from primary and recurrent GBM- Combined treatment significantly prolongs survival in vivo- Combined treatment potentially targets the quiescent GBM cell populationImportance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

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Current Trends in Glioblastoma Multiforme Treatment: Radiation Therapy and Immune Checkpoint Inhibitors

Cited by 16 publications

References 85 publications

Prospects of immune checkpoint modulators in the treatment of glioblastoma

Prospects of immune checkpoint modulators in the treatment of glioblastoma

Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model

Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

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