Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

Pearson, Joshua R.D.; Cuzzubbo, Stefania; McArthur, Simon; Durrant, Lindy G.; Adhikaree, Jason; Tinsley, Chris J.; Pockley, A. Graham; McArdle, Stephanie E.B.

doi:10.3389/fimmu.2020.582106

Cited by 61 publications

(46 citation statements)

References 243 publications

(243 reference statements)

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“…The propensity for glioblastoma tumors to quickly adapt through antigen escape remains a major barrier to CAR T cell therapy ( Figure 1 ) ( 132 ). To minimize the risk of treatment resistance, it is likely that CAR T cells should target multiple antigens or be combined with a synergistic therapy.…”

Section: Immune Privilege and The Central Nervous System: A Case For Immunotherapymentioning

confidence: 99%

Immunotherapy for Glioblastoma: Current Progress and Challenges

Quail

2021

Front. Immunol.

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Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.

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Section: Immune Privilege and The Central Nervous System: A Case For Immunotherapymentioning

confidence: 99%

Immunotherapy for Glioblastoma: Current Progress and Challenges

Quail

2021

Front. Immunol.

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“…Despite this aggressive treatment regimen, long-term survival remains poor due to the persistence of radioresistant GSCs [43,44]. Other approaches in development include immunotherapies, which have been gamechangers in heme malignancies but disappointed in solid tumors such as GBM [45], and oncolytic virus, which has shown promise when combined with immunotherapies [46]. However, directly targeting GSCs remains extremely challenging and there are still no approved drugs targeting GSCs [6].…”

Section: Discussionmentioning

confidence: 99%

Downregulated CLIP3 induces radioresistance by enhancing stemness and glycolytic flux in glioblastoma

Kang

Lee

Kim

et al. 2021

J Exp Clin Cancer Res

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Background Glioblastoma Multiforme (GBM) is a malignant primary brain tumor in which the standard treatment, ionizing radiation (IR), achieves a median survival of about 15 months. GBM harbors glioblastoma stem-like cells (GSCs), which play a crucial role in therapeutic resistance and recurrence. Methods Patient-derived GSCs, GBM cell lines, intracranial GBM xenografts, and GBM sections were used to measure mRNA and protein expression and determine the related molecular mechanisms by qRT-PCR, immunoblot, immunoprecipitation, immunofluorescence, OCR, ECAR, live-cell imaging, and immunohistochemistry. Orthotopic GBM xenograft models were applied to investigate tumor inhibitory effects of glimepiride combined with radiotherapy. Results We report that GSCs that survive standard treatment radiation upregulate Speedy/RINGO cell cycle regulator family member A (Spy1) and downregulate CAP-Gly domain containing linker protein 3 (CLIP3, also known as CLIPR-59). We discovered that Spy1 activation and CLIP3 inhibition coordinately shift GBM cell glucose metabolism to favor glycolysis via two cellular processes: transcriptional regulation of CLIP3 and facilitating Glucose transporter 3 (GLUT3) trafficking to cellular membranes in GBM cells. Importantly, in combination with IR, glimepiride, an FDA-approved medication used to treat type 2 diabetes mellitus, disrupts GSCs maintenance and suppresses glycolytic activity by restoring CLIP3 function. In addition, combining radiotherapy and glimepiride significantly reduced GBM growth and improved survival in a GBM orthotopic xenograft mouse model. Conclusions Our data suggest that radioresistant GBM cells exhibit enhanced stemness and glycolytic activity mediated by the Spy1-CLIP3 axis. Thus, glimepiride could be an attractive strategy for overcoming radioresistance and recurrence by rescuing CLIP3 expression.

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“…Multiple factors are associated with this low response rate: (i) limited immunogenicity and (ii) local immunosuppression. Translational research may help identification of predictive biomarkers [ 84 , 85 ]. Recently conducted major phase III clinical trials are reported in Table 2 .…”

Section: Summary Of Major Phase III Clinical Trialsmentioning

confidence: 99%

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

Birzu

French

Caccese

et al. 2020

Cancers

117

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Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients.

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Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

Cited by 61 publications

References 243 publications

Immunotherapy for Glioblastoma: Current Progress and Challenges

Immunotherapy for Glioblastoma: Current Progress and Challenges

Downregulated CLIP3 induces radioresistance by enhancing stemness and glycolytic flux in glioblastoma

Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives

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