Investigational treatment strategies in glioblastoma: progress made and barriers to success

ABSTRACT

Introduction

Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings.

Areas Covered

Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables.

Expert Opinion

Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.

KEYWORDS:

• Cancer neuroscience
• cancer vaccination
• chimeric antigen receptor T-cell therapy
• glioblastoma
• immunotherapy

Article highlights

• Glioblastoma, IDH wildtype, (GBM) affects more than 12,000 individuals per year in the US with an estimated worldwide increasing incidence of 0.5-5 per 100,000, and existing therapies are not curative

• Trials of brachytherapy, chemotherapy-impregnated wafers, high-dose chemotherapy, molecular-targeted therapies, anti-angiogenesis, and immune checkpoint inhibition have not resulted in changes to present management

• Evolving understanding of GBM due to molecular characterization, genomics, and cancer neuroscience has the potential to improve outcomes

• Recent work has demonstrated the potential benefit of dendritic cell and peptide GBM vaccines as well as CAR T-cell therapies

• Many trials are underway of immunotherapy- and non-immunotherapy-based regimens, including those targeting neural hyperexcitability, tumor metabolism, and neuro-immune signaling

• A multimodality, multi-pathway treatment regimen has the greatest likelihood of durable response in GBM but will require creative trial design on a solid scientific foundation

Declaration of interests

JD has been a consultant for Amgen, Novartis, and Ono Therapeutics. JD also has received royalties as an author for UpToDate. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed roles on the advisory board and speaker’s bureau for Merck and Novocure and the advisory board for AstraZeneca and Cardinal Health. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

TN is supported by the National Institutes of Health (2K12CA090354-21), but this paper was not funded.