Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

Abstract

Glioblastoma (GBM) is an immunosuppressive, lethal brain tumor. Despite advances in molecular understanding and therapies, the clinical benefits have remained limited, and the life expectancy of patients with GBM has only been extended to~15 months. Currently, genetically modified oncolytic viruses (OV) that express immunomodulatory transgenes constitute a research hot spot in the field of glioma treatment. An oncolytic virus is designed to selectively target, infect, and replicate in tumor cells while sparing normal tissues. Moreover, many studies have shown therapeutic advantages, and recent clinical trials have demonstrated the safety and efficacy of their usage. However, the therapeutic efficacy of oncolytic viruses alone is limited, while oncolytic viruses expressing immunomodulatory transgenes are more potent inducers of immunity and enhance immune cell-mediated antitumor immune responses in GBM. An increasing number of basic studies on oncolytic viruses encoding immunomodulatory transgene therapy for malignant gliomas have yielded beneficial outcomes. Oncolytic viruses that are armed with immunomodulatory transgenes remain promising as a therapy against malignant gliomas and will undoubtedly provide new insights into possible clinical uses or strategies. In this review, we summarize the research advances related to oncolytic viruses that express immunomodulatory transgenes, as well as potential treatment pitfalls in patients with malignant gliomas. Facts Open questions 1. Can the immune system attack and engulf exogenous viruses? 2. Are glioma stem cells resistant to viral therapy? 3. Can the presence of nontumor cells such as tumor stroma cells impede the spread of oncolytic viruses? 4. In personalized medicine, should potential challenges be considered for the treatment of patients with malignant gliomas?

Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes

“…OVs drive tumor cell death, resulting in the release of inflammatory signals (cell stress danger-associated molecular patterns or DAMPS) and the liberation of tumor-associated antigens to promote anti-tumor immunity. Most recently, clinical trials in patients with brain tumors have shown promising results using OVs ( 144 ), such as PVSRIPO (a modified poliovirus OV) in patients with glioblastoma, where some patients have shown complete and durable remissions ( 145 ). Future investigations into combinatorial approaches may further enhance the outcomes of OVs in tumors and help delineate which patients with brain tumors may require additional resections vs. orthogonal treatment combinations.…”

Perspective of mesenchymal transformation in glioblastoma

“…Oncolytic virotherapy may also circumvent mesenchymal transition in GBM by promoting the polarization state of TAMs as pro-inflammatory and antitumoral M1 phenotype. As it was discussed in the recent review by Zhang and Liu, genetically modified oncolytic viruses expressing immunomodulatory transgenes have been considered as a promising therapeutic tool for glioma treatment [ 182 ]. Combined treatment of oncolytic herpes simplex virus expressing IL-12 with two checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) resulted in the regression of GBM tumor in a preclinical mouse model and, interestingly, this treatment was found to be associated with influx of macrophages of M1-like polarization state [ 132 ].…”

WITHDRAWN: Ribosomal Protein S27-Like is overexpressed in glioma cells and inhibition of RPS27L expression suspends the tumorigenesis

“…Gliomas can be divided into various subtypes according to their histological characteristics [4]. Although great progress has been made in the diagnosis and treatment of glioma in the past decades, the prognosis is still poor [5,6]. The 5-year survival rate of low-grade glioma patients is about 30 ~ 70%, while the median survival time of GBM patients is 9 ~ 12 months [7,8].…”