Immunotherapy for Glioblastoma: Current Progress and Challenges

Yu, Miranda W.; Quail, Daniela F.

doi:10.3389/fimmu.2021.676301

Cited by 107 publications

(99 citation statements)

References 135 publications

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“…Here, we detailed clinical and preclinical advances in immune checkpoint blockade, vaccination strategies and emerging CAR T cell therapies for the treatment of GBM ( Figure 1 ). Among the major hurdles to clinical efficacy are immense intratumoral heterogeneity [ 6 , 7 ], parallel modes of immunosuppression by tumor cells [ 121 , 122 , 123 ] and low mutational burden in GBM [ 124 ]. With these factors in mind, investigators and clinicians are shifting their focus to combinatorial and personalized treatment strategies to achieve synergistic effects, reduce treatment resistance and overcome immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Advances in Immunotherapy for Adult Glioblastoma

Chokshi

Brakel

Tatari

et al. 2021

Cancers

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Despite aggressive multimodal therapy, glioblastoma (GBM) remains the most common malignant primary brain tumor in adults. With the advent of therapies that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients.

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Section: Discussionmentioning

confidence: 99%

Advances in Immunotherapy for Adult Glioblastoma

Chokshi

Brakel

Tatari

et al. 2021

Cancers

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“…Patients with GBM have a very poor prognosis, with an average overall survival of merely 12–15 months [ 5 ]. In spite of recent advances in standard treatment, including surgery, chemotherapy, radiotherapy, and the achievement in targeted therapies and immunotherapies over the past several years, GBM still carries a dismal prognosis with poor survival [ 6 – 10 ]. Therefore, novel prognostic approaches to pick out patients with high risks are warranted to further help therapeutic options for GBM patients.…”

Section: Introductionmentioning

confidence: 99%

Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

Cao

2022

BMC Cancer

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Background Glioblastoma (GBM) is considered the most malignant and devastating intracranial tumor without effective treatment. Autophagy, apoptosis, and necrosis, three classically known cell death pathways, can provide novel clinical and immunological insights, which may assist in designing personalized therapeutics. In this study, we developed and validated an effective signature based on autophagy-, apoptosis- and necrosis-related genes for prognostic implications in GBM patients. Methods Variations in the expression of genes involved in autophagy, apoptosis and necrosis were explored in 518 GBM patients from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox analysis were performed to construct a combined prognostic signature. Kaplan–Meier survival, receiver-operating characteristic (ROC) curves and Cox regression analyses based on overall survival (OS) and progression-free survival (PFS) were conducted to estimate the independent prognostic performance of the gene signature. The Chinese Glioma Genome Atlas (CGGA) dataset was used for external validation. Finally, we investigated the differences in the immune microenvironment between different prognostic groups and predicted potential compounds targeting each group. Results A 16-gene cell death index (CDI) was established. Patients were clustered into either the high risk or the low risk groups according to the CDI score, and those in the low risk group presented significantly longer OS and PFS than the high CDI group. ROC curves demonstrated outstanding performance of the gene signature in both the training and validation groups. Furthermore, immune cell analysis identified higher infiltration of neutrophils, macrophages, Treg, T helper cells, and aDCs, and lower infiltration of B cells in the high CDI group. Interestingly, this group also showed lower expression levels of immune checkpoint molecules PDCD1 and CD200, and higher expression levels of PDCD1LG2, CD86, CD48 and IDO1. Conclusion Our study proposes that the CDI signature can be utilized as a prognostic predictor and may guide patients’ selection for preferential use of immunotherapy in GBM.

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“…Glioblastoma is a Grade IV glioma and the most common primary malignant brain tumor, which, in addition to its high mortality rate and low median survival, is also resistant to all current conventional immunotherapy agents 1 . Therefore, the mainstay of glioblastoma therapy remains surgery with concomitant temozolomide (TMZ) and radiation followed by adjuvant TMZ.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions

Kopecký

Pérez

Eriksson

et al. 2022

Sci Rep

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Glioblastoma has remained the deadliest primary brain tumor while its current therapy offers only modest survival prolongation. Immunotherapy has failed to record notable benefits in routine glioblastoma treatment. Conventionally, immunotherapy relies on T cells as tumor-killing agents; however, T cells are outnumbered by macrophages in glioblastoma microenvironment. In this study, we explore the effect of AF16, a peptide from the endogenous antisecretory factor protein, on the survival of glioma-bearing mice, the tumor size, and characteristics of the tumor microenvironment with specific focus on macrophages. We elucidate the effect of AF16 on the inflammation-related secretome of human and murine macrophages, as well as human glioblastoma cells. In our results, AF16 alone and in combination with temozolomide leads to cure in immunocompetent mice with orthotopic GL261 gliomas, as well as prolonged survival in immunocompromised mice. We recorded decreased tumor size and changes in infiltration of macrophages and T cells in the murine glioma microenvironment. Human and murine macrophages increased expression of proinflammatory markers in response to AF16 treatment and the same effect was seen in human primary glioblastoma cells. In summary, we present AF16 as an immunomodulatory factor stimulating pro-inflammatory macrophages with a potential to be implemented in glioblastoma treatment protocols.

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Immunotherapy for Glioblastoma: Current Progress and Challenges

Cited by 107 publications

References 135 publications

Advances in Immunotherapy for Adult Glioblastoma

Advances in Immunotherapy for Adult Glioblastoma

Prognostic value and immune relevancy of a combined autophagy-, apoptosis- and necrosis-related gene signature in glioblastoma

Intratumoral administration of the antisecretory peptide AF16 cures murine gliomas and modulates macrophage functions

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