Strategic Insights into Oncolytic Virus Product Development by Professor Su Changqing of Naval Medical University

Oncolytic viruses (OVs) have garnered increasing attention from both the scientific community and the industry due to their ability to selectively replicate within tumor cells and induce lysis without affecting normal cells. Compared with other therapies, oncolytic virus therapy is characterized by high replication efficiency, potent cytotoxic effects, and minimal toxic side effects, making it a new focal point in the field of cancer treatment research.

As of now, four oncolytic virus therapies have been approved for marketing worldwide: Rigvir (ECHO-7 virus), Oncorine (recombinant human adenovirus type 5), T-Vec (herpes simplex virus), and Delytact (herpes simplex virus).

Notably, since approving T-Vec in 2015, the FDA has not approved any other oncolytic virus products. Oncolytic virus research has a century-long history,Due to the failure to address inherent deficiencies of natural viruses, such as lack of targeting specificity and pathogenicity, therapeutic efficacy in relevant indications has remained suboptimal, which is one of the reasons for the relatively slow progress of oncolytic virus therapy.

At the recently held 4th Oncolytic Virus Drug Development Conference in 2023, Professor Su Changqing from the National Center for Liver Cancer Science at Naval Medical University delivered a presentation titled “Reflections on Key Issues in the Development of Oncolytic Virus Products.” In his speech, he analyzed and discussed the development history of oncolytic viruses, clinical progress, and key issues that the industry should focus on in the future.

The following are the key points summarized from Professor Su Changqing’s lecture:

Currently, the global incidence of cancer remains high and is showing a rapid upward trend. In this context, China ranks first worldwide in both cancer incidence and mortality rates, which are 3.5 times those of India, a country with a comparable population size.

In China, there is still a certain gap compared to foreign countries in the application of anti-tumor therapies. Abroad, advanced targeted drugs and immunotherapies dominate, accounting for 60% of oncology treatments. In China, clinical practice remains predominantly reliant on chemotherapy, which constitutes 63% of treatments. This significant disparity in medication usage represents the key focus and market opportunity for Chinese pharmaceutical companies in new drug development.

The development of novel anti-tumor drugs has progressed through distinct stages, from chemotherapy to targeted therapy, and further to immunotherapy. Around 1997, targeted therapies achieved a significant breakthrough driven by milestone advances in the Human Genome Project. In 2013, the international journal Science ranked progress in tumor immunology research and cancer immunotherapy as the top item among its Top Ten Breakthroughs of the Year, marking a new breakthrough for immunotherapy.

Subsequently, in 2014, the world’s first PD-1 inhibitor was approved for market launch. Immune checkpoint inhibitors and oncolytic virus therapies have since risen to prominence.

Throughout the development of all novel oncology drugs, oncolytic virus therapy has emerged as a significant direction. It combines the characteristics of targeted therapy and immunotherapy, offering numerous advantages:

• Oncolytic viruses can enhance the regulation of tumor-targeting genes and their oncolytic effects, while minimizing their impact on normal cells;

• After oncolytic viruses destroy tumor cells, they release important tumor antigens as well as structural proteins expressed by the virus itself; these are delivered to the immune system via antigen-presenting cells, thereby eliciting an immune response.

• Oncolytic viruses also possess the characteristics of gene therapy; they can be engineered to carry immune genes, antibody genes, and other genetic payloads, as well as to express specific tumor neoantigens.

• Due to the high molecular weight and strong immunogenicity of oncolytic virus vectors, they can also serve as adjuvants to realize the concept of cancer vaccines.

Therefore, oncolytic virotherapy integrates multiple therapeutic concepts, making its clinical application highly promising.

Currently, the global research and development of oncolytic viruses is experiencing rapid growth, with the United States, China, Canada, Germany, and Japan ranking among the leaders.

The industry is developing a variety of oncolytic viruses, including both natural viral strains and genetically engineered viral strains.Among genetically engineered viral strains, herpes simplex virus, poxvirus, and adenovirus account for a relatively high proportion. Compared with naturally occurring viral strains, genetically engineered strains are more precisely targeted in terms of the specific tumor cells to be addressed and the anti-tumor agents to be delivered, thereby ensuring regulated control of target genes and potent anti-tumor activity, so as to maximize their therapeutic value within a controllable safety profile.

In terms of tumor types, oncolytic viruses are predominantly based on herpes simplex virus (HSV) and adenovirus. Among the four approved oncolytic virus products, one is an adenovirus-based therapy, and two are HSV-based therapies. Currently, clinical development of oncolytic virus products has made significant progress, demonstrating favorable long-term efficacy in trials. In China, Funuo Health, ImmuneOnco, and BinHui Biotherapeutics are at the forefront of research and development.

For the research and development of oncolytic virus therapies, safety, efficacy, and industrialization deserve greater attention.

In enhancing the targeting performance of viruses, the industry has given considerable consideration, primarily focusing on the quantitative regulation of viral targeting or proliferation genes, with measures varying across different types of viruses.

In terms of arming with exogenous genes, most current oncolytic virus R&D still adopts a vector strategy to achieve efficient expression of oncolytic factors while inducing oncolysis, thereby exerting a dual oncolytic effect.

In terms of delivery routes, oncolytic viruses can be administered via various methods, including intratumoral injection, intraperitoneal injection, and intravenous injection.Intratumoral injection remains the mainstream approach.It not only leverages the advantage of localized tumor ablation but also evades immune-mediated viral clearance, thereby avoiding toxicity risks to non-target cells and achieving maximal local viral concentration for superior therapeutic efficacy.

Currently,The industry is also intensifying its R&D efforts on intravenous injection to improve drug accessibility.Not only can clinicians avoid complex procedures, but patient acceptance will also be higher. However, the key lies in addressing the risks of rapid viral load dilution and interception by neutralizing antibodies in vivo.

Nowadays,Oncolytic Virus Combination Therapy: The Prevailing Trend.Among registered clinical trials of oncolytic viruses, only one involves monotherapy, while the rest are combination therapies, including those combined with chemotherapy and immunotherapy. In the context of combination cancer therapy, oncolytic viruses are poised to serve as a versatile enhancer across multiple treatment modalities.

However, even with synergistic effects, it is necessary to consider the synergistic enhancement among various mechanisms. Only by taking multiple factors into account can better therapeutic efficacy be achieved.

Professor Su Changqing’s research group is innovating in the field of oncolytic viruses by developing three serotype-chimeric oncolytic adenoviruses. These vectors not only enhance viral recognition and infection potency against tumor cells but also evade neutralization by antibodies. Furthermore, the team constructed composite promoters to regulate viral replication, achieving stringent control at both transcriptional and translational levels. They engineered the viruses to carry three classes of factors—interleukins, interferons, and chemokines—to realize a synergistic mechanism. Interleukins and interferons promote T-cell proliferation and potentiate the efficacy of immune checkpoint inhibitors, while chemokines recruit additional T cells into the tumor microenvironment for cytotoxic activity.

Currently, the research team has conducted preclinical experimental validation across various animal models, demonstrating that this product holds significant therapeutic potential. We look forward to the emergence of outstanding clinical data for this product in the future.