Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas

Abstract

The prognosis of malignant gliomas remains poor, with median survival fewer than 20 months and a 5-year survival rate merely 5%. Their primary location in the central nervous system (CNS) and its immunosuppressive environment with little T cell infiltration has rendered cancer therapies mostly ineffective, and breakthrough therapies such as immune checkpoint inhibitors (ICIs) have shown limited benefit. However, tumor immunotherapy is developing rapidly and can help overcome these obstacles. But for now, malignant gliomas remain fatal with short survival and limited therapeutic options. Oncolytic virotherapy (OVT) is a unique antitumor immunotherapy wherein viruses selectively or preferentially kill tumor cells, replicate and spread through tumors while inducing antitumor immune responses. OVTs can also recondition the tumor microenvironment and improve the efficacy of other immunotherapies by escalating the infiltration of immune cells into tumors. Some OVTs can penetrate the blood-brain barrier (BBB) and possess tropism for the CNS, enabling intravenous delivery. Despite the therapeutic potential displayed by oncolytic viruses (OVs), optimizing OVT has proved challenging in clinical development, and marketing approvals for OVTs have been rare. In June 2021 however, as a genetically engineered OV based on herpes simplex virus-1 (G47Δ), teserpaturev got conditional and time-limited approval for the treatment of malignant gliomas in Japan. In this review, we summarize the current state of OVT, the synergistic effect of OVT in combination with other immunotherapies as well as the hurdles to successful clinical use. We also provide some suggestions to overcome the challenges in treating of gliomas.

Agent-based computational modeling of glioblastoma predicts that stromal density is central to oncolytic virus efficacy

“…Notwithstanding this, OVs hold promise owing to their multimodal mode of action and their possibility of arming with genes that improve replication and spread, decrease tumor vascularisation, and elicit strong antitumor immune responses. The approval of TVEC (Imlygic) for the treatment of melanoma and more recently teserpaturev for the treatment of glioma is further evidence of the potential effectiveness of this therapy ( Kaufman et al., 2022 ; Yuan et al., 2022 ; Zeng et al., 2021 ).…”

Glioblastoma Treatment: State-of-the-Art and Future Perspectives

“…At first, this therapy was developed for direct destruction of tumoral cells, but it has shown a wider range of potential applications. OV immunologic mechanisms include the release of tumor antigens (DAMPs), inhibition of tumoral immunosuppressive genes, transport of pro-inflammatory agents to tumoral cells, and tumoral microenvironmental disruption, among other factors that favor T-cell infiltration and a more effective immune response against the tumor (Figure 2) [18,49,63,[70][71][72][73].…”

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

“…Additionally, the most thoroughly investigated therapies delivered the suicide genes thymidine kinase or cytosine deaminase (toca 511) rather than agents that may more directly modulate the local immune landscape. There are promising agents on the horizon in preclinical, phase 1, and phase 2 studies that directly deliver immunomodulatory agents such as ad-RTS-hil-12, interferon beta, VB111 (discussed below), tesurpaterev ( 64 ), RLI, and others ( 59 , 62 , 65 ).…”