Glioblastoma treatment slowly moves toward change: novel druggable targets and translational horizons in 2022

ABSTRACT

Introduction

Glioblastoma (GBM) is the most common primary brain tumor in adults. GBM treatment options have been the same for the past 30 years and have only modestly extended survival, despite aggressive multimodal treatments. The progressively better knowledge of GBM biology and a comprehensive analysis of its genomic profile have elucidated GBM heterogeneity, contributing to a more effective molecular classification and to the development of innovative targeted therapeutic approaches.

Areas covered

This article reports all the noteworthy innovations for immunotherapy and targeted therapy, providing insights into the current advances in trial designs, including combination therapies with immuno-oncology agents and target combinations.

Expert opinion

GBM molecular heterogeneity and brain anatomical characteristics critically restrain drug effectiveness. Nevertheless, stimulating insights for future research and drug development come from innovative treatment strategies for GBM, such as multi-specific ‘off-the-shelf’ CAR-T therapy, oncolytic viral therapy and autologous dendritic cell vaccination. Disappointing results from targeted therapies-clinical trials are mainly due to complex interferences between signaling pathways and biological processes leading to drug resistance: hence, it is imperative in the future to develop combinatorial approaches and multimodal therapies.

KEYWORDS:

• Glioblastoma
• immunotherapy
• bevacizumab
• regorafenib
• CAR T cells
• NTRK
• larotrectinib
• buparlisib
• dendritic cell vaccine
• oncolytic virotherapy
• toca 511

Article highlights

• GBM is the most aggressive primary malignant tumor of the central nervous system (CNS), exhibiting poor survival despite multimodal treatment, with a median survival of 12–18 months.

• Despite the countless clinical trials conducted in the last decade, GBM is refractory to improvements in treatment: even the most promising therapeutic agents demonstrated high rates of failure in clinical trials. The main causes of these failures are GBM molecular heterogeneity, a ‘cold’ immunosuppressive microenvironment and the presence of the blood-brain barrier (BBB) which hinders drugs penetration within brain tissue.

• Among the treatments worthy of more attention and further research is tumor treating fields (TTF) device, that, despite FDA approval, currently, still finds limited application in clinical practice, especially in Europe.

• Regarding immunotherapy, after failure of immune-checkpoints inhibitors to demonstrate survival advantage as single agents, dendritic cell vaccine (DCVax-L) seems to be a really promising immunotherapeutic agent, having shown great efficacy in prolonging survival and great adaptability.

• The field of targeted therapies is growing fervently: the search for specific biomarkers predictors of response and the availability of combinatorial approaches overcoming the complex interferences between different signaling pathways seem to be winning strategies to make these drugs more and more effective.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.