Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice

Abstract

Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials.

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

“…Many oncolytic viruses have been tested and proven to be safe in the clinic for glioblastoma multiforme treatment (4,24). Despite encouraging safety results there are many factors like virus delivery, anti-virus immune response, intratumoral spread of infection that still need to be addressed to significantly improve efficacy, and make oncolytic virus therapies for glioblastoma multiforme a reality (25,26).…”

“…Herpes simplex virus, adenovirus, and Newcastle disease virus have been evaluated in phases I and II clinical trials for treatment of glioblastoma multiforme. They show excellent safety data but have so far not resulted in successful tumor shrinkage and prolonged survival (4). Adenovirus has been used to treat children with neuroblastoma with encouraging results (5,6).…”

Exploring the antitumor effect of virus in malignant glioma

“…TK-negative oncolytic HSV (oHSV) was tested in human glioblastoma models, both in vitro and in vivo in mice, but found to be insufficiently attenuated (22). Since then, many OVs have been used in hundreds of preclinical studies in many different cancer models, and a number of clinical trials have been completed or are currently running that have demonstrated safety, as well as provided indications of effective antitumor activity against glioma (21, 23–25). OVs replicate selectively in and kill cancer cells sparing normal cells (21).…”

“…OV targeting of cancer cells doesn't usually involve specific genetic alterations, in contrast to molecularly targeted drugs, but rather targets more general features of the transformed phenotype, such as defective anti-viral/innate responses, cell cycle controls, and apoptosis induction. Because OVs utilize multiple avenues to destroy tumors (ie,, oncolysis of cancer cells, induction of multiple cell death pathways, in situ amplification and spread, induction of specific antitumor immune responses, destruction of tumor vasculature) they are attractive candidates for the treatment of malignant glioma (23–25, 28). In this review, we will focus on those OVs that have been in clinical trials for the treatment of malignant glioma and OVs examined preclinically.…”

Conjugation of pH-responsive nanoparticles to neural stem cells improves intratumoral therapy

“…[12–14] NSCs can penetrate even to hypoxic tumor regions, overcoming high interstitial pressures and stiff extracellular matrices. [15, 16] NSCs have also been modified to distribute therapeutic payloads for tumor killing[17–19]. One therapeutic approach involves an enzyme-prodrug strategy in which the NSCs are genetically engineered to produce the enzyme cytosine deaminase which locally converts the prodrug 5-flurocyosine (5-FC) into the active chemotherapeutic 5-fluorouracil (5-FU)[12].…”