The battle of the ages: Cancer vs Virus

By Jessie Ng Chi Wai

An oncolytic virus is a type of replicable virus which infects and kills cancer cells. Oncolytic virus therapy is now highly regarded among cancer treatments, as it has shown excellent capability in stimulating an immune response against cancer without causing harm to other healthy tissues.

         Reports of viral infections reducing cancerous tumours have been emerging since the 20th century (Kabiljo, Laengle and Bergmann, 2020). The first case was recorded in 1904, where an infection of influenza A caused a complete tumour remission (Kabiljo, Laengle and Bergmann, 2020). Researchers further consolidated this effect of influenza A as an oncolytic virus in preclinical settings. However, the understanding of virology was not sufficiently advanced for clinical application – and so, the safe use of oncolytic viruses for cancer treatment was not possible at the time (Kabiljo, Laengle and Bergmann, 2020).

         In the early 1990s, virus engineering was in full swing, and gene therapy based on viruses was underway for severe combined immunodeficiency, liver failure, and haemophilia. Furthermore, ethical concerns around clinical trials which involved oncolytic viruses were beginning to dampen. In 1991, Science published a study which reported the application of an engineered herpes simplex virus (HSV)- an oncolytic virus- for treating malignant gliomas (Martuza et al., 1991). This marked the beginning of oncolytic viruses being used as a potential treatment for cancer.

         However, the application of such a powerful weapon against cancer did not always go so smoothly. The world’s first commercialized oncolytic virus product, Oncorine (H101), was approved by Chinese SFDA in 2005 after its phase III clinical trials and then acquired its GMP certificate in 2006 (Liang, 2018).  It was designed to treat nasopharyngeal carcinoma together with conventional chemotherapy. However, the therapeutic effects of such combined treatment were not quite satisfactory and Oncrine slowly faded from public attention (Liang, 2018). It was not until 2015 that the US FDA approved the use of talimogene laherparepvec (T-VEC, a.k.a. OncoVEXGM-CSF), which is an oncolytic virus, for melanoma immunotherapy (Pol, Kroemer and Galluzzi, 2015). It was at this point that oncolytic viruses joined the battle for combating cancer.

         However, there were also imperfections in oncolytic virus immunotherapy. The oncolytic virus alone cannot completely fight off cancers. The fundamental reason for this is that every cancer patient has a different sensitivity and reactivity to the oncolytic virus. Therefore, in order to ensure that patients can benefit from the treatment, it is of paramount importance to recognize the host cell factors required for infectivity and oncolysis.

         On 22nd June, 2021, researchers from the German Cancer Research Center (DKFZ) and the Laboratory of Oncolytic Virus Immuno-Therapeutics (LOVIT) published a paper titled “Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry” (Kulkarni et al., 2021). This study demonstrated viral entry via laminins and showed how H-1 parvovirus (H-1PV) adheres and attacks cancer cells to cause their oncolysis and death. 

To maximize the effectiveness of oncolytic viruses, it is therefore crucial to identify and recognize biomarkers which can indicate the cancer cells’ susceptibility to H-1PV treatment. Kulkarni et al. carried out siRNA library screening by using a druggable genome library and identified an essential modulator of H-1PV infection, laminin γ1 (LAMC1). 

Fundamentally, when the specific region of a virus interacts with that of a cancer cell, laminin (on the surface of the cancer cell) would act as a “door”, helping the virus to locate, adhere to and destroy the cancer cells. By presenting evidence of the direct correlation between LAMC1 expression levels and the oncolytic activity of H-1PV in 59 different cancer cell lines, this study demonstrated that virus-induced oncolysis would be reduced in glioma, cervical cancer, pancreatic cancer, colorectal cancer and lung cancer patients.

         The clinical significance of these novel findings was evaluated. Researchers pointed out the difference in laminin expression levels in different tumour microenvironments. Compared to healthy tissues, laminin is commonly seen overexpressed in pancreatic cancer and glioblastoma multiforme (GBM). Moreover, in brain tumours, the expression of laminin was found to have elevated in correlation with successive stages of metastasis – where GBMs have been shown to express higher levels of laminin. This relationship was confirmed with protein tissue microarray performed on 110 GBM biopsies, showing that recurrent GBM had higher laminin levels compared to primary GBM.

It is important to note that normal tissues also express laminins even though at a much lower level compared to tumour cells. This would then be able to explain why healthy cells can be infected by H-1PV. Fortunately, these infections would not lead to the lysis of normal cells or the generation of progeny particles as healthy cells lack essential factors for viral replication of H-1PV. 

Laminins have shown to be one of the important modulators of viral infectivity of H-1PV, but this alone is not sufficient for the prediction of the H-1PV treatment outcome as laminins have shown to involve in cell attachment and entry but there various other cellular factors that modulate the entry and post-entry mechanisms of H-1PV infections. These cellular modulators have yet to be identified. 

         In recent years, mature pharmaceutical manufacturers are increasingly investing in the research and development of oncolytic virus immunotherapy. This latest discovery will help in the design of future clinical trials – and in turn, reduce the cost and time taken for drug approval. This will improve the therapeutic options for cancer patients and oncolytic virus immunotherapy may become a common treatment approach for patients with advanced cancer prognosis. However, it would still be of significant importance for researchers to identify the genes of other biomarkers which could be predictive and prognostic markers to update the clinical management and enhance the patient survival and recovery rate. 

Figure 1. A visual representation of the interaction between H-1PV and laminin during viral entry.

Diagram

Description automatically generated

 γ1 chains of laminin form heterotrimer complexes with α (1–5) chains and β (1–4) chains. Researchers found that laminins are crucial for the attachment H-1PV at cell surface. 

References:

Kabiljo, J., Laengle, J. and Bergmann, M. (2020). From threat to cure: understanding of virus-induced cell death leads to highly immunogenic oncolytic influenza viruses. Cell Death Discovery, 6(1).

Kulkarni, A., Ferreira, T., Bretscher, C., Grewenig, A., El-Andaloussi, N., Bonifati, S., Marttila, T., Palissot, V., Hossain, J.A., Azuaje, F., Miletic, H., Ystaas, L.A.R., Golebiewska, A., Niclou, S.P., Roeth, R., Niesler, B., Weiss, A., Brino, L. and Marchini, A. (2021). Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry. Nature Communications, 12(1).

Liang, M. (2018). Oncorine, the World First Oncolytic Virus Medicine and its Update in China. Current Cancer Drug Targets, 18(2).

Martuza, R.L., Malick, A., Markert, J.M., Ruffner, K.L. and Coen, D.M. (1991). Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science (New York, N.Y.), [online] 252(5007), pp.854–6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/1851332 [Accessed 5 Dec. 2019].

Pol, J., Kroemer, G. and Galluzzi, L. (2015). First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology, [online] 5(1). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760283/ [Accessed 19 Mar. 2020].

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