Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Stupp, Roger; Hegi, Monika E.; Mason, Warren P.; Bent, Martin J. van den; Taphoorn, Martin J.B.; Janzer, Robert C.; Ludwin, Samuel K.; Allgeier, Anouk; Fisher, Barbara; Bélanger, Karl; Hau, Peter; Brandes, Alba A.; Gijtenbeek, J.M.M.; Marosi, Christine; Vecht, Charles J.; Mokhtari, Karima; Wesseling, Pieter; Villà, Salvador; Eisenhauer, Elizabeth; Gorlia, Thierry; Weller, Michael; Lacombe, Denis; Cairncross, J. Gregory; Mirimanoff, René-Olivier

doi:10.1016/s1470-2045(09)70025-7

Cited by 6,804 publications

(5,374 citation statements)

References 45 publications

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“…With the current standard of care, which includes maximal surgical resection plus adjuvant chemotherapy and radiation, median survival is still less than two years. 1-3 Thus, efforts are currently underway to identify novel therapies for the treatment of GBM. One therapeutic approach, immunotherapy, modulates the host immune response to cancer to eradicate tumors.…”

Section: Introductionmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

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Section: Introductionmentioning

confidence: 99%

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

et al. 2018

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“…To our surprise, samples in the grade II-III TMA were not significantly different than those in the non-neoplastic tissue TMA, but had significantly fewer CD163+ cells than either grade I or GBM (Figure 1B, C). Compared to GBM, which has an overall 5-year survival of 9.8%, 1 patients diagnosed with grade I pilocytic astrocytoma have a favorable outcome: 96.5% 5-year survival in patients 5–19, and 52.9% in patients over 60. 24 While future studies with larger cohorts will be needed to confirm these findings, this data indicates that although accumulation of CD163 expressing cells may predict survival within grade III patient populations, 23 it does not correlate with prognosis across all grades.…”

Section: Resultsmentioning

confidence: 98%

“…1 The infiltrative nature of tumor cells into surrounding brain tissue and distant sites makes complete microscopic surgical resection improbable and recurrence inevitable, necessitating an immune therapy that can effectively eliminate transformed cells while leaving surrounding neural and glial structures intact.…”

Section: Introductionmentioning

confidence: 99%

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

et al. 2018

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Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue.Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

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“…Despite recent advances in understanding of its pathogenesis, GBM remains incurable with standard treatment options contributing little to survival time. Currently, GBM has a 5‐year survival rate of only 10% and a median survival time of 15 months following treatment 1, 2. Contributing to its poor prognosis are numerous therapeutic challenges including aggressive growth rates, tumor heterogeneity, drug resistance, and obstacles to drug delivery such as the blood–brain barrier.…”

Section: Introductionmentioning

confidence: 99%

“…Currently, the standard treatment for newly diagnosed GBM is cytoreductive surgery followed by concurrent radiation and chemotherapy with TMZ 2. However, even the most successful treatment plans are only palliative, aiming to delay relapse for as long as possible.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

Harish²,

et al. 2016

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Glioblastoma multiforme (GBM) is the most common and lethal cancer of the adult brain, remaining incurable with a median survival time of only 15 months. In an effort to identify new targets for GBM diagnostics and therapeutics, recent studies have focused on molecular phenotyping of GBM subtypes. This has resulted in mounting interest in microRNAs (miRNAs) due to their regulatory capacities in both normal development and in pathological conditions such as cancer. miRNAs have a wide range of targets, allowing them to modulate many pathways critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis, and drug resistance. This review explores our current understanding of miRNAs that are differentially modulated and pathologically involved in GBM as well as the current state of miRNA‐based therapeutics. As the role of miRNAs in GBM becomes more well understood and novel delivery methods are developed and optimized, miRNA‐based therapies could provide a critical step forward in cancer treatment.

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Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

Cited by 6,804 publications

References 45 publications

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

MicroRNAs in glioblastoma multiforme pathogenesis and therapeutics

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