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; glioblastoma; high-grade glioma; viral vectors.

Figure 1.

Viral vectors being tested in clinical trials for HGG.

Figure 2.

(1) Oncolytic viruses (OV) infect glioma cells, initiating the process of immunogenic cell death (ICD). Dying glioma cells release damage associated molecular patterns (DAMP) and type I interferons, molecules that stimulate the host’s immune response. Following the virus-mediated lysis of the cell, oncolytic virus is released into the surrounding tissue and can infect adjacent glioma cells. (2) Tumor-associated antigens (TAA) recruit immature antigen-presenting cells (APC) to the tumor. (3) APC become activated following antigen-uptake and begin interacting with DAMP via pattern recognition receptors (toll-like receptors (TLR) and nod-like receptors (NLR)). (4) Following this interaction, immature antigen-capturing APC become mature APC, which are able to form and transport peptide-loaded MHC complexes to the cell surface. (5) Mature APC migrate to a regional lymph node where they prime naïve T cells. This is followed by clonal expansion and then release of cytotoxic CD8⁺ T lymphocytes (CTL). (6) These tumor specific CTL are attracted to the tumor by cytokines released from dying glioma cells. Natural killer (NK) cells, part of the innate immune system, are attracted to the tumor by chemokine. Altogether, this generates an anti-tumor immune response. (7) Continuous exposure of TAA to CTL promotes immunological memory, generating memory CD8⁺ T cells.