Immunotherapy for brain metastases and primary brain tumors

Giacomo, Anna Maria Di; Mair, Maximilian J.; Ceccarelli, Michele; Anichini, Andrea; Ibrahim, Ramy; Weller, Michael; Lahn, Michael; Eggermont, Alexander; Fox, Bernard A.; Maio, Michele

doi:10.1016/j.ejca.2022.11.012

Cited by 16 publications

(8 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In light of these considerations, it is crucial to explore new strategies that enhance treatment response and improve the survival prospects and quality of life for GBM patients. Recent evidence has highlighted biological differences between primary and secondary brain tumors, emphasizing variations in tumor-infiltrating lymphocytes, the absence of immune checkpoint expression, and lower tumor mutational burden in patients with GBM compared to BM [14]. However, in-depth molecular analyses of the intrinsic characteristics of tumors derived from GBM and BM are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…However, the clinical failures of ICI therapy in GBM cannot be entirely attributed to the immune specialization of the brain, as patients with BM from extracranial primary tumors showed responses to ICI. Beyond tumor cell-intrinsic effects (e.g., type of driver mutations), several pronounced differences between GBM and BM have been discovered, demonstrating an abundance of tumorassociated macrophages, tissue-resident microglia, and monocyte-derived macrophages recruited from the peripheral circulation, and a paucity of tumor-infiltrating CD3 + lymphocytes and of immune checkpoints expression [14] in GBM compared to BM [15]. Thus, tumors that arise within the brain actually shape their TME differently than tumors that metastasize to the brain from extracranial sites.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

Lofiego,

Piazzini,

Caruso

et al. 2024

J Transl Med

Self Cite

View full text Add to dashboard Cite

Background Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM. Methods Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients’ cohort. Results The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways. Conclusions Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

Lofiego,

Piazzini,

Caruso

et al. 2024

J Transl Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…Though the current evidence shows no treatment benefits of immunotherapy for newly diagnosed glioma patients [ 120 , 121 ], great progress in translational immunotherapy for recurrent glioma has been made in recent years. Multiple immune regimes, especially combination therapies, have been proved to be safe and tolerated.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Immunotherapy for Recurrent Glioma—From Bench to Bedside

Zhou

Zhao

et al. 2023

Cancers

View full text Add to dashboard Cite

Glioma is the most aggressive malignant tumor of the central nervous system, and most patients suffer from a recurrence. Unfortunately, recurrent glioma often becomes resistant to established chemotherapy and radiotherapy treatments. Immunotherapy, a rapidly developing anti-tumor therapy, has shown a potential value in treating recurrent glioma. Multiple immune strategies have been explored. The most-used ones are immune checkpoint blockade (ICB) antibodies, which are barely effective in monotherapy. However, when combined with other immunotherapy, especially with anti-angiogenesis antibodies, ICB has shown encouraging efficacy and enhanced anti-tumor immune response. Oncolytic viruses and CAR-T therapies have shown promising results in recurrent glioma through multiple mechanisms. Vaccination strategies and immune-cell-based immunotherapies are promising in some subgroups of patients, and multiple new tumor antigenic targets have been discovered. In this review, we discuss current applicable immunotherapies and related mechanisms for recurrent glioma, focusing on multiple preclinical models and clinical trials in the last 5 years. Through reviewing the current combination of immune strategies, we would like to provide substantive thoughts for further novel therapeutic regimes treating recurrent glioma.

show abstract

“…Clinically, BrM are more responsive to ICB compared with rGBM ( 10 ). In fact, BrM respond to ICB treatment at a rate similar to that of patient-matched extracranial lesions.…”

Section: Introductionmentioning

confidence: 99%

“…The difference in ICB response rates between BrM and rGBM has been linked to the baseline immune microenvironment differences of the 2 brain tumor types ( 10 ). In comparison with the tumor microenvironment (TME) of rGBM, T cells in BrM exhibited a greater activation and exhaustion phenotype ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors

Sun,

Kienzler,

Reynoso

et al. 2023

Journal of Clinical Investigation

View full text Add to dashboard Cite

In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206 + macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB’s effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.

show abstract

Immunotherapy for brain metastases and primary brain tumors

Cited by 16 publications

References 66 publications

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches

Immunotherapy for Recurrent Glioma—From Bench to Bedside

Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors

Contact Info

Product

Resources

About