Radiation and Immunotherapy in High-grade Gliomas

Reznik, Elizabeth; Smith, Andrew W.; Taube, Shoshana; Mann, Jack; Yondorf, M.; Parashar, Bhupesh; Wernicke, A. Gabriella

doi:10.1097/coc.0000000000000406

Cited by 26 publications

(23 citation statements)

References 80 publications

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“…The immune microenvironment has been identified as playing a critical role in tumor biology (Hanahan and Weinberg, 2011), and recently, numerous promising preclinical and clinical immunotherapeutic treatments, including immune-checkpoint inhibitors, active or passive immunotherapy, and gene therapy, have been achieved in malignant gliomas (Mahmoodzadeh Hosseini et al, 2015;Xu et al, 2015;Reznik et al, 2018;Simonelli et al, 2018;Vismara et al, 2019), further establishing the vital role of immunotherapy in the management of gliomas. Hence, the molecular profiles of the immune components within the tumor microenvironments represent tremendous value in serving as prognostic biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

et al. 2020

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Objective: Despite several clinicopathological factors being integrated as prognostic biomarkers, the individual variants and risk stratification have not been fully elucidated in lower grade glioma (LGG). With the prevalence of gene expression profiling in LGG, and based on the critical role of the immune microenvironment, the aim of our study was to develop an immune-related signature for risk stratification and prognosis prediction in LGG. Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA), Genome Tissue Expression (GTEx), and Chinese Glioma Genome Atlas (CGGA) were used. Immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort). Univariate, multivariate cox regression, and Lasso regression were employed to identify differentially expressed immune-related genes (DEGs) and establish the signature. A nomogram was constructed, and its performance was evaluated by Harrell's concordance index (C-index), receiver operating characteristic (ROC), and calibration curves. Relationships between the risk score and tumor-infiltrating immune cell abundances were evaluated using CIBERSORTx and TIMER. Results: Noted, 277 immune-related DEGs were identified. Consecutively, 6 immune genes (CANX, HSPA1B, KLRC2, PSMC6, RFXAP, and TAP1) were identified as risk signature and Kaplan-Meier curve, ROC curve, and risk plot verified its performance in TCGA and CGGA datasets. Univariate and multivariate Cox regression indicated that the risk group was an independent predictor in primary LGG. The prognostic signature showed fair accuracy for 3-and 5-year overall survival in both internal (TCGA) and external (CGGA) validation cohorts. However, predictive performance was poor in the recurrent LGG cohort. The CIBERSORTx algorithm revealed that naïve CD4 + T cells were significant higher in low-risk group. Conversely, the infiltration levels of

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Section: Introductionmentioning

confidence: 99%

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

et al. 2020

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“…With the current standard approach of concomitant and adjuvant TMZ, it might not matter which RT procedure is chosen. With new treatment approaches such as TTF or immunotherapy 55 , 56 , 57 , the role of adjuvant radiotherapy will be further defined.…”

Section: Introductionmentioning

confidence: 99%

Radiotherapy of glioblastoma 15 years after the landmark Stupp’s trial: more controversies than standards?

Kazda

Dziacky

Burkoň

et al. 2018

Radiology and Oncology

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BackgroundThe current standard of care of glioblastoma, the most common primary brain tumor in adults, has remained unchanged for over a decade. Nevertheless, some improvements in patient outcomes have occurred as a consequence of modern surgery, improved radiotherapy and up-to-date management of toxicity. Patients from control arms (receiving standard concurrent chemoradiotherapy and adjuvant chemotherapy with temozolomide) of recent clinical trials achieve better outcomes compared to the median survival of 14.6 months reported in Stupp’s landmark clinical trial in 2005. The approach to radiotherapy that emerged from Stupp’s trial, which continues to be a basis for the current standard of care, is no longer applicable and there is a need to develop updated guidelines for radiotherapy within the daily clinical practice that address or at least acknowledge existing controversies in the planning of radiotherapy.The goal of this review is to provoke critical thinking about potentially controversial aspects in the radiotherapy of glioblastoma, including among others the issue of target definitions, simultaneously integrated boost technique, and hippocampal sparing.ConclusionsIn conjunction with new treatment approaches such as tumor-treating fields (TTF) and immunotherapy, the role of adjuvant radiotherapy will be further defined. The personalized approach in daily radiotherapy practice is enabled with modern radiotherapy systems.

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“…However, the median survival for GBM patients has only marginally improved over the past two decades when these drugs have been available. Checkpoint inhibitory and cellular immunotherapies have yet to exhibit any significant alteration in progression free or overall survival (43,44). If we cannot enhance the immune system to attack GBM tumor cells, we reasoned, our initial conceptual approach became instead to attack the immune cell-rich soil in which the GBM tumor cells require to grow, thereby suppressing tumor cell growth and invasion, and with the hope that this will also enhance the lethality of standard of care therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

et al. 2020

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Previously we demonstrated that the multiple sclerosis drug dimethyl fumarate (DMF) and its plasma breakdown product MMF could interact with chemotherapeutic agents to kill both GBM cells and activated microglia. The trial NCT02337426 demonstrated the safety of DMF in newly diagnosed GBM patients when combined with the standard of care Stupp protocol. We hypothesized that another multiple sclerosis drug, fingolimod (FTY720) would synergize with MMF to kill GBM cells. MMF and fingolimod interacted in a greater than additive fashion to kill PDX GBM isolates. MMF and fingolimod radiosensitized glioma cells and enhanced the lethality of temozolomide. Exposure to [MMF + fingolimod] activated an ATM-dependent toxic autophagy pathway, enhanced protective endoplasmic reticulum stress signaling, and inactivated protective PI3K, STAT, and YAP function. The drug combination reduced the expression of protective c-FLIP-s, MCL-1, BCL-XL, and in parallel caused cell-surface clustering of the death receptor CD95. Knock down of CD95 or over-expression of c-FLIP-s or BCL-XL suppressed killing. Fingolimod and MMF interacted in a greater than additive fashion to rapidly enhance reactive oxygen species production and over-expression of either thioredoxin or super-oxide dismutase two significantly reduced the drug-induced phosphorylation of ATM, autophagosome formation and [MMF + fingolimod] lethality. In contrast, the production of ROS was only marginally reduced in cells lacking ATM, CD95, or Beclin1. Collectively, our data demonstrate that the primary generation of ROS by [MMF + fingolimod] plays a key role, via the induction of toxic autophagy and death receptor signaling, in the killing of GBM cells.

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Radiation and Immunotherapy in High-grade Gliomas

Cited by 26 publications

References 80 publications

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

Novel Immune-Related Gene Signature for Risk Stratification and Prognosis of Survival in Lower-Grade Glioma

Radiotherapy of glioblastoma 15 years after the landmark Stupp’s trial: more controversies than standards?

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

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