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Over the past few decades, immunotherapy has emerged as an effective therapeutic option against multiple malignancies. Oncolytic viruses (OVs) can be engineered to selectively replicate in and lyse tumor tissues while sparing the normal non-neoplastic host cells and simultaneously restoring antitumor immunity, which offers a novel immunotherapeutic approach for the treatment of tumors.

Despite the potential of OVs, there are still many limitations that should be tackled to improve their efficacy in virotherapy. These include factors such as viral tropism, delivery platforms, viral distribution, dosing strategies, antiviral immunity, etc.

Choosing the Optimal OV

A wide range of different viral species has been investigated as prospective cancer therapeutic agents, including oncolytic adenoviruses, type 1 herpes simplex virus (HSV), polioviruses, measles virus (MV), Newcastle disease virus (NDV), reoviruses, vesicular stomatitis virus (VSV), and Zika virus. Given different kinds of tumors of diverse histologic origins, although some viruses exhibit a native tropism for tumors, they cannot readily match given OVs specifically with a certain kind of malignancy.

The envelope and size of the OV, tumor tropism, potential pathogenicity, immunogenicity, druggability, and viral stability are important factors to be considered in virus selection.

Retargeting OVs

To enhance an OV’s tropism and to reduce its adverse effects, different technologies varying from genetics to chemistry have been used to retarget OVs, and some are being evaluated in clinical trials. Retargeting approaches can be divided into three main categories: capsid development, genome engineering, and chemical modifications.

However, there is still insufficient knowledge on each OV’s surface binding, internalization, and gene expression properties.

Constructing Efficient OV Delivery Platforms

Although the greatest effect of OVs consists of their selective infection and replication in cancer cells, the ability to deliver OV particles efficiently to tumors still constitutes a huge hindrance. The rapid growth of tumors, impaired blood supply, abnormal lymphatic networks, vascular hyperpermeability inside tumors, the dense extracellular matrix (ECM) of solid tumors, and the antiviral functions of the host’s immune system all reduce the efficacy and delivery of OVs.

Maintaining the Balance between Antiviral Immunity and Antitumor Immunity

Another challenge is the presence of innate and adaptive antiviral immune responses evoked by OVs, which can lead to the quick clearance of OVs and limit their antitumor efficacy. Multiple strategies have been envisaged to suppress antiviral immunity, including the use of immunomodulators, genetic manipulation, antioxidant sulforaphane, cytokines, etc.

However, some investigators advocate that OV-induced antiviral immune responses are beneficial to antitumor immunity because they can overturn tumor-associated immunosuppression, and lead to virus-induced immunogenic cell death, thereby activating antitumor immunity. Thus, it’s necessary to develop strategies to manage antiviral immunity, to enhance antitumor immune activity, and to maintain the balance between them.

Oncolytic virotherapy is a promising immunotherapy for malignancies. With the development of modern genetic engineering techniques, increasing numbers of researchers are discovering strategies to optimize the construction of OVs, to reduce their clinical toxicity, to construct efficient OV delivery platforms, and to increase the efficacy of OVs, with the aim of achieving the greatest therapeutic benefit.

The latest research also found that oncolytic virotherapy can be combined with other treatments such as immunosuppressive drugs, which shows a better outcome in tumor treatment. It’s believed that such combination therapy could be new hope for patients suffering from cancer.