Oncolytic viruses (OVs) are considered particularly promising due to their dual modes of action: they can both eliminate infected tumor cells and stimulate anti-tumor immunity, which promotes the destruction of uninfected tumor cells. Additionally, they have various collateral effects that can enhance existing tumor therapies. However, the history of commercial success associated with oncolytic virotherapy is relatively brief. While some adenovirus-based oncolytic therapies have received regulatory approval in China and other countries, the first oncolytic drug to gain approval from the FDA and EMA, which garnered significant industry attention, was Amgen's Talimogene laherparepvec (T-VEC) in 2015. T-VEC is a recombinant HSV-1 oncolytic virus. The most recently approved oncolytic therapy is teserpaturev, also known as G47Δ (DELYTACT?), developed by Daiichi Sankyo. This modified HSV-1 received conditional and time-limited approval for the treatment of malignant glioma in Japan in June 2021.

Although the successful commercialization of oncolytic viruses as immunotherapies is relatively recent, the underlying science is quite established. Researchers have been investigating viruses as anti-tumor agents since scientists first noted that some patients with active microbial and viral infections experienced a slowdown in tumor progression. Over the past few decades, this observation of natural pathogens has been applied to a variety of engineered viruses, including HSV-1, adenovirus, poliovirus, measles virus, and others. Our understanding of the mechanisms of action of these viruses has also steadily advanced. In addition to approved products, several viral oncolytic therapies developed using various viral platforms are currently undergoing clinical trials, many of which are yielding extremely promising results.

Current research on oncolytic virus design focuses on viruses with various transgenes to enhance their immunostimulatory effects, modulate immune checkpoints, and provide imaging targets. By synergizing oncolytic viruses with other immunomodulators or cytotoxic agents, drug developers aim to achieve the most effective tumor immunotherapy. Although researchers continue to optimize these viruses and their production through various viral engineering strategies, they face several challenges related to safety, efficacy, and commercial scale-up. Key obstacles include achieving high viral yields, ensuring highly reproducible critical quality attributes, maintaining genetic stability, and meeting formulation and product stability goals.

One of the challenges hindering the development of these therapies is ensuring the relative safety of the viral vectors. Most oncolytic viruses replicate conditionally or partially, primarily within tumor cells. Minimizing the potential for the virus to replicate in healthy cells is a key consideration during early clinical trials. This enhanced safety profile underscores the significance of the early stages of viral vector design, from cell line selection to infection optimization. For biopharmaceuticals that can replicate independently, even those restricted to specific cell types or cell cycle stages, it is crucial to ensure that the virus cannot revert to a fully replication-competent form in order to advance the therapy through development.

Vector design and engineering, along with other elements of early product development, are essential for minimizing the risk of off-target cellular replication or expression of the drug product after administration to patients. Proper vector design is crucial; poorly designed vectors or the use of non-optimized cell lines can result in genetic instability, including the potential production of fully replication-competent viruses and the emergence of transgenic variants or subtypes that may impact viral efficacy and safety. Additionally, the selection of cell lines, culture types, media, supplements, infection optimization, and early downstream harvest processes significantly influences viral yield and purity, necessitating a comprehensive and multifaceted approach. Notably, the choice of media used for cell culture should not compromise safety or productivity, making media selection a vital component for ensuring optimal scale-up.

Moreover, due to the significant differences between different oncolytic viruses, the manufacturing processes need to be designed according to the characteristics of each virus. But, in general, the virus production process starts with the selection of production cell lines, including adherent or suspension cell culture, cell lysis, virus purification, and may need to adopt sterile process, the latter is especially important for viruses with larger particle sizes, such as poxviruses, which cannot be sterilized by filtration through the same steps as adenoviruses and other small non-enveloped viruses. As with other viral vector-based products, facilities require the highest level of GMP compliance and commitment to sterility and use single-use components and even fully closed systems wherever possible to prevent any potential cross-contamination.

In addition, as mentioned earlier, since there are only a few approved oncolytic virus therapies on the market, the regulatory environment surrounding them remains relatively unstable, and oncolytic virus vector design needs to pay attention to the changing regulatory requirements applicable to these therapies. Since each virus used in oncolytic virus applications has unique characteristics, unique approval paths specific to different oncolytic virus products may appear based on the selected virus and mode of action. At the same time, although testing viral vectors for vaccine and oncolytic applications is largely consistent, there are also some key differences: Typically, oncolytic viruses have additional active recombinant components, usually immunomodulatory, and therefore require more in-depth testing, that is, confirming the effectiveness and safety of oncolytic virus products may require new analytical testing strategies.

In summary, oncolytic viruses have shown good safety and efficacy in clinical trials, and great progress has been made in translating them into clinical practice, especially in addressing some challenges. Genetic engineering strategies have helped improve the safety and efficacy of oncolytic viruses. In addition, it is currently believed that oncolytic viruses can work in a variety of ways in addition to direct tumor cell disruption, such as genetic engineering that makes it possible to add immunomodulators and marker genes. Some studies have shown that oncolytic viruses and other existing tumor therapies, such as immunomodulators, can work synergistically to optimize therapeutic effects and overcome potential resistance to any single treatment mode.

A variety of oncolytic viruses are currently undergoing clinical development, and many factors are still under consideration, including routes of administration and optimal drug combinations. Although there are currently few approved products and most ongoing trials are in relatively early stages, given the effectiveness and specificity of oncolytic viruses, more oncolytic virus products are expected to be approved by regulators in the next few years. This offers great potential to broaden the range of treatment options available for patients with various tumors.

Duoning Biotech provides comprehensive single-use solutions for each key step of the oncolytic virus process, including preparation systems for different types and volumes of buffer solutions required for each process unit, silicone tubes and peristaltic pump tubes for fluid transfer management, as well as weldable thermoplastic tubes and welder, sealer for the needs of aseptic operating environments; single-use liquid storage bags and containers for intermediate storage and transfer, and we can provide customized, pre-assembled tube sets specially designed for different systems of chromatography, ultrafiltration/diafiltration and other critical unit operations according to customer requirements to speed up operations.

Duoning Biotech's oncolytic virus bioprocess solution can help accelerate product development and significantly reduce cost of goods, thereby improving product availability and benefiting more patients.