Oncolytic viruses (OVs) are considered particularly promising because they have two main modes of action: they can both kill infected tumor cells and stimulate antitumor immunity to promote the development of antitumor immunity against uninfected tumor cells. killing. In addition, there are other associated effects. Because of this, they offer the possibility of greatly enhancing existing tumor therapies. However, the history of commercial success associated with oncolytic virus therapy is relatively short. Although some adenovirus-based oncolytic virus therapy has been approved by regulatory agencies in China and other countries earlier, the first one to obtain FDA and EMA approval and cause the industry's broader focus on oncolytic therapies came in 2015 with Amgen's Talimogene laherparepvec (T-VEC), a recombinant HSV-1 oncolytic virus, and the more recent approval was teserpaturev from Daiichi Sankyo. or G47Δ (DELYTACT?), also a modified form of HSV-1, received conditional and time-limited approval in Japan for glioblastoma in June 2021.

Although the successful commercialization of oncolytic viruses as immunotherapies is relatively new, the science at their core has a long history, since scientists first observed slowed tumor progression in some patients with live microbial and viral infections. Researchers have already begun to explore viruses as anti-cancer tools. Over the past few decades, this observation of natural pathogens has been applied to a range of engineered viruses, including HSV-1, adenovirus, poliovirus, measles virus, and others. The understanding of how these viruses work is also steadily improving. In addition to approved products, many viral oncolytic therapies built using various viral platforms are currently undergoing clinical trials, many of which have shown promising results.

Current research on oncolytic virus design has focused on "arming" oncolytic viruses with various transgenes to increase their immune stimulation, modulate immune checkpoints, and provide imaging targets. By striving to synergize oncolytic viruses with other immunomodulators or cytotoxic agents, developers hope to achieve the most effective tumor immunotherapy. Although researchers are continuing to optimize these viruses and their production through various virus engineering strategies, many goals related to the safety, efficacy, and commercial scale-up of such products are challenging their way forward, including how to achieve high virus yield, highly reproducible critical quality attributes, genetic stability, and formulation and product stability.

One challenge that slowing the development of these therapies is ensuring the relative safety of viral vectors. Most oncolytic viruses replicate conditionally or partially mainly in tumor cells, and minimizing the possibility of viral replication in healthy cells is a primary consideration in early clinical trials. This increased safety highlights the importance of the early stages of viral vector design, from cell line selection to infection optimization. For biotherapeutics that can replicate themselves, even those that are restricted to specific cell types or cell cycle stages, ensuring that the virus cannot revert to full replication competence is critical to advancing therapeutics through the development process.

Vector design and engineering, in conjunction with other aspects of early product development, are critical to reducing the possibility of off-target cell replication or expression after a drug product is administered to a patient. Proper vector design is critical. Improperly designed vectors, or the use of non-optimized cell lines, can lead to genetic instability, including the potential to produce fully replicative viruses, as well as the potential to produce transgenic variants or subtypes that affect viral efficacy and safety. Likewise, the impact of cell line selection, culture type, media, supplements, infection optimization, and early downstream harvest processes on virus yield and purity requires an integrated, multifaceted approach. In particular, the choice of media used to grow cells should not affect their safety and productivity, so media selection becomes an important part of ensuring optimal scale-up.

Moreover, due to the significant differences among different oncolytic viruses, it is necessary to design a targeted production process according to the characteristics of each virus. In general, however, the virus production process begins with production cell line selection, including growth in adherent or suspension culture, cell lysis, media and buffer optimization, virus purification, and aseptic production, the latter is especially important for viruses with larger particle size. Viruses, such as vaccina, cannot be sterile filtered through the same steps as adenoviruses and other small non-enveloped viruses. As with other viral vector-based products, manufacturing facilities require the highest level of commitment to GMP compliance and sterility, employing single-use technologies and even closed systems wherever possible to prevent any potential cross-contamination.

Furthermore, as mentioned previously, since only a few approved oncolytic viral therapies currently exist on the market, the regulatory environment surrounding them remains relatively fluid, and oncolytic viral vector design requires attention to the ever-changing regulatory requirements applicable to these therapies , as each virus used in oncolytic virus applications has unique characteristics, unique approval paths may arise that are specific to different oncolytic virus products based on the chosen virus and mode of action. At the same time, while virus vectors tested for vaccine and oncolytic applications are largely consistent, there are some key differences: Typically, oncolytic viruses have additional active recombinant components, usually immunomodulatory, and thus require more in-depth testing, that is, confirmation of efficacy and safety of oncolytic virus products may require new analytical testing strategies.