Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults

Abstract

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of the introduction of either wild-type or engineered viruses to the site of disease, where they exert an antitumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induces tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights the potential to integrate this therapeutic strategy into promising combinatory approaches.

Investigational Microbiological Therapy for Glioma

“…The natural hosts of H-1PV are rodents, which have the ability to infect and replicate in humans, but lack pathogenicity. H-1PV interacts with galectin-1 on the cell surface and uses this glycoprotein to enter cancer cells [ 57 ], and its tumorolytic mechanism of action is thought to work through the cathepsin-mediated cell death pathway, so it may be an effective therapeutic approach for targeting glioma cells with defects in the apoptotic pathway [ 58 ]. It is able to cross the blood–brain barrier and therefore has potential for intravenous administration [ 59 ].…”

Immunotherapy Resistance in Glioblastoma

“…Many of these mutated constructs are designed to allow preferential infection and lysis of tumor cells, allowing for viral propagation and stimulation of an immune response via release of tumor antigens (Yin et al, 2017). Two main HSV mutants tested in clinical trials for GBM are G207, capable of replicating in only dividing cells, and HSV1716, which can replicate in both dividing and nondividing cells (Immidisetti et al, 2021). There have been three phase I trials that demonstrated the safety and tolerability of G207 in rGBM and ndGBM patients (Markert et al, 2000;Markert et al, 2009;Markert et al, 2014), and similarly, three phase I trials have shown HSV1716 to be tolerable in ndGBM and rGBM patients (Rampling et al, 2000;Papanastassiou et al, 2002;Harrow et al,…”

Assembly of Multiple Full‐Size Genes or Genomic DNA Fragments on Human Artificial Chromosomes Using the Iterative Integration System

“…One of the methods relies on transfection of BAC DNA carrying a gene(s) of interest into host cells (Arii, Kato, Kawaguchi, Tohya, & Akashi, 2009; Auriche et al., 2010; Hall et al., 2008; Head et al., 2007; Hibbitt et al., 2007; Illenye et al., 2004; Poser et al., 2008; Tsuji et al., 2006). Another popular approach is based on transduction with viruses or virus‐based delivery vectors carrying small‐sized genes (not bigger than 5 kb) or cDNA (Gimpel et al., 2021; Huang et al., 2021; Immidisetti, Nwagwu, Adamson, Patel, & Carbonell, 2021; Ma, Hill, Hoang, & Wen, 2021; Mijanović et al., 2020; Wang, Scheitler, Wenger, & Elder, 2021; Zhang, Wu, Zhang, & Xia, 2021). Both methods, however, may lead to random integrations of BACs or viruses into host chromosomes.…”