Oncolytic herpes simplex viruses for the treatment of glioma and targeting glioblastoma stem-like cells

Abstract

Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover, oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of oHSV therapy.

Advances in oncolytic herpes simplex virus and adenovirus therapy for recurrent glioma

“…The immune response, responsible for clearing OVs and hindering their replication, is a major reason for the effectiveness of oncolytic virotherapy. Combining OVs with immunosuppressants, such as anti-PD1 antibodies, has shown promise in clinical trials (137). Achieving a balance between immune response and clearance through the use of immunosuppressants and multi-dose OVs delivery requires further investigation.…”

Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives

“…Compared to the normal cellular microenvironment, TME is characterized by hypoxia, low pH, high interstitial pressure, high vascular permeability, and an inflammatory response; TME is closely related to GC resistance to TMZ, and long‐term use of TMZ may exacerbate immunosuppression in glioma TME. 81 , 82 Angiogenic factors are particularly active in glioma TME, including transforming growth factor beta, hypoxia‐inducible factor, cyclooxygenase‐2, fibroblast growth factor, and helper T cell 2 cytokines. 83 , 84 Inhibition of the production of angiogenic factors, especially in glioma TME, and blocking the blood supply to the tumor are targets of action of many antiangiogenic agents.…”

Combination of Oncolytic Virotherapy with Different Antitumor Approaches against Glioblastoma

“…When its deleted, HSV-1 cannot complete lytic infection in neurons and thus does not cause encephalitis. Upon inactivation of ICP6, encoding a large subunit of ribonucleotide reductase (RR), the virus is able to replicate only in actively proliferating cells (e.g., tumor cells) with high levels of host RR [39]. In Phase 1 of a clinical trial, G207 showed a strong effect against pediatric high-grade gliomas.…”

“…In preclinical studies, the only oncolytic virus approved for use in patients with glioblastoma, G47∆, was evaluated in combination with etoposide [18,39]. Etoposide is a semi-synthetic derivative of podophyllotoxin.…”

“…Moreover, the life expectancy of tumor-bearing mice treated with this combination was higher compared to that of the monotherapy and control groups. G47∆ has also been studied in combination with temozolomide [19,39]. The joint action is characterized by synergy both in vitro and in vivo.…”