Gene Therapy for High Grade Glioma: The Clinical Experience

ABSTRACT

Introduction

High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of ~18 months. The standard of care (SOC) is maximal safe surgical resection, and radiation therapy with concurrent and adjuvant temozolomide. This protocol remains unchanged since 2005, even though HGG median survival has marginally improved.

Areas covered

Gene therapy was developed as a promising approach to treat HGG. Here, we review completed and ongoing clinical trials employing viral and non-viral vectors for adult and pediatric HGG, as well as the key supporting preclinical data.

Expert opinion

These therapies have proven safe, and pre- and post-treatment tissue analyses demonstrated tumor cell lysis, increased immune cell infiltration, and increased systemic immune function. Although viral therapy in clinical trials has not yet significantly extended the survival of HGG, promising strategies are being tested. Oncolytic HSV vectors have shown promising results for both adult and pediatric HGG. A recently published study demonstrated that HG47Δ improved survival in recurrent HGG. Likewise, PVSRIPO has shown survival improvement compared to historical controls. It is likely that further analysis of these trials will stimulate the development of new administration protocols, and new therapeutic combinations that will improve HGG prognosis.

KEYWORDS:

• Gene therapy
• viral vectors
• glioblastoma
• high-grade glioma

Article highlights

• High-grade gliomas (HGG) standard of care (SOC) remains unchanged since 2005, even though HGG median survival has marginally improved.

• There are currently over 20 clinical trials using gene therapy to treat HGG.

• Administration of HSV-1 G207 showed promising results in HGG and pediatric HGG.

• HSV-1 rQNestin offers a safer treatment option with a strong support for preclinical data.

• HSV-1 G47Δ was able to improve survival and received government approval in Japan.

• PVSRIPO showed an improvement in HGG survival compared to the historical controls.

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 funded by ChadTough Foundation (grant G023419), Ian’s Friends Foundation (grant G024230), Leah’s Happy Hearts Foundation (grant G013908), National Cancer Institute (NIH/NCI) (grant U01CA224160), National Institute of Biomedical Imaging and Bioengineering (grant R01-EB022563), National Institute of Neurological Disorders and Stroke (grants R01-NS074387, R01-NS076991, R01-NS082311, R01-NS096756, R01-NS105556, R21-NS091555, R21-NS107894, R37-NS094804, R01-NS122234, R01-NS127378), Pediatric Brain Tumor Foundation (grant G023387), RNA Biomedicine (grant F046166) and Rogel Cancer Center at The University of Michigan (grant G023089).