Identifying Chemical Enhancers for Oncolytic Virotherapy in Treatment of Gliomas
Background: Glioma refers broadly to neuroepithelial tumors originating from the glial or supporting cells of the central nervous system1. Gliomas are the most common malignant brain tumor in the United States,2 making up almost 80% of all intracranial malignant tumors3. Glioblastoma multiforme (GBM), the most aggressive form of glioma, is associated with a very poor prognosis and significant long-term morbidity4. Traditional standards of care, such as chemotherapy and surgical resection, have only modestly improved outcomes over several decades4 because glioma is typically resistant to these conventional therapeutics5. As a result, oncolytic virotherapy (OV) emerged as a novel treatment for gliomas and GBM4 that works by injecting an engineered virus into cancerous tumors, thus activating the immune functions and inducing apoptosis of tumor cells3.
Objective: This review looks at the recent standards of care in treatment of gliomas and the emerging use of oncolytic virotherapy (OV), then assesses benefits, drawbacks, and potential improvements to OV to help improve the quality of life and prognosis for glioma patients – “the most pressing challenge in neuro-oncology5.”
Search Methods: An online search of the PubMed database revealed relevant research within the past 5 years.
Results: Multiple research studies have indicated promising results in improving GBM prognosis using oncolytic viruses such as ZIKV-LAV (a live attenuated Zika virus) and G47Δ (a triple-mutated oncolytic herpes simplex virus type 1). ZIKV-LAV infection evoked antiviral immunity, inflammation, and glioblastoma stem cell apoptosis, and greatly decreased intracerebral tumor growth and prolonged survival after intracerebral injection in treated animals6. In a Phase I/II clinical trial, G47Δ infection led to tumor cell destruction via viral replication and lymphocyte infiltration towards tumor cells7.
However, despite promising research into oncolytic virotherapy, research suggests it frequently fails because GBM cells are usually nonpermissive to OV8. Additional research into overcoming this barrier explores the combination of OV with other anti-cancer agents, such as immune checkpoint inhibitors, that demonstrate improved therapeutic efficacy9.
For example, co-administering PD-L1/PD-1 checkpoint blockade enhanced ICOVIR17 virotherapy and increased survival compared to control virus, ICOVIR15. ICOVIR17 promoted tumor-infiltrating CD8+ T cells and macrophages, and upregulated PD-L1 on glioblastoma cells and macrophages10. Similarly, research indicates that Anti-EGFR-CCL5 fusion proteins enhance oHSV oncolytic virotherapy. Infection of GBM significantly enhanced the migration and activation of natural killer cells, macrophages, and T cells, and inhibited tumor EGFR signaling, reduced tumor size, and prolonged survival with GBM in tumor-bearing mice11. Furthermore, CDK4/6 inhibition selectively increases the potency of VSVΔ51 oncolytic virus by inducing severe DNA damage stress and amplifying the breakdown of cancer cells. It greatly inhibited tumor growth and synergistically induced immunogenic cell death and boosted antitumor immunity8.
Conclusion: These studies show some of the promise behind combined treatment approaches to improve glioma prognosis but warrant further investigation. Additional understanding of the tumor microenvironment and mechanisms of resistance to oncolytic virotherapy are pivotal for future research efforts4.
- Davis ME. Epidemiology and Overview of Gliomas. Semin Oncol Nurs. 2018;34(5):420-429. doi:10.1016/j.soncn.2018.10.001
- Ostrom QT, Cote DJ, Ascha M, Kruchko C, Barnholtz-Sloan JS. Adult Glioma Incidence and Survival by Race or Ethnicity in the United States From 2000 to 2014. JAMA Oncol. 2018;4(9):1254–1262. doi:10.1001/jamaoncol.2018.1789
- Li J, Meng Q, Zhou X, et al. Gospel of malignant Glioma: Oncolytic virus therapy. Gene. 2022;818:146217. doi:10.1016/j.gene.2022.146217
- Ghajar-Rahimi G, Kang KD, Totsch SK, et al. Clinical advances in oncolytic virotherapy for pediatric brain tumors. Pharmacol Ther. 2022;239:108193. doi:10.1016/j.pharmthera.2022.108193
- Carpenter AB, Carpenter AM, Aiken R, Hanft S. Oncolytic virus in gliomas: a review of human clinical investigations. Ann Oncol. 2021;32(8):968-982. doi:10.1016/j.annonc.2021.03.197
- Chen Q, Wu J, Ye Q, et al. Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate. mBio. 2018;9(5):e01683-18. Published 2018 Sep 18. doi:10.1128/mBio.01683-18
- Todo, T., Ino, Y., Ohtsu, H. et al. A phase I/II study of triple-mutated oncolytic herpes virus G47∆ in patients with progressive glioblastoma. Nat Commun 13, 4119 (2022). https://doi.org/10.1038/s41467-022-31262-y
- Xiao J, Liang J, Fan J, et al. CDK4/6 Inhibition Enhances Oncolytic Virus Efficacy by Potentiating Tumor-Selective Cell Killing and T-cell Activation in Refractory Glioblastoma. Cancer Res. 2022;82(18):3359-3374. doi:10.1158/0008-5472.CAN-21-3656
- Rius-Rocabert S, García-Romero N, García A, Ayuso-Sacido A, Nistal-Villan E. Oncolytic Virotherapy in Glioma Tumors. Int J Mol Sci. 2020;21(20):7604. Published 2020 Oct 14. doi:10.3390/ijms21207604
- Kiyokawa J, Kawamura Y, Ghouse SM, et al. Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma. Clin Cancer Res. 2021;27(3):889-902. doi:10.1158/1078-0432.CCR-20-2400
- Tian, L., Xu, B., Chen, Y. et al. Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity. Nat Cancer 3, 1318–1335 (2022). https://doi.org/10.1038/s43018-022-00448-0