The potential of viruses to selectively infect and kill cancer cells was first recognised over a century ago. However, translating this potential into effective cancer treatments has proven to be exceptionally challenging.
After decades of research and innovation, the pieces may finally be falling into place for the next generation of oncolytic viruses (OVs) to finally break through as cancer therapies.
A Century of Discovery and Development
The origins of oncolytic virotherapy (OVT) can be traced back to the late 19th century when physicians observed that cancer patients who contracted infectious diseases sometimes experienced tumour regression. This suggested a link between viral infection and tumour suppression.
Building on the early observations, researchers deliberately infected cancer patients with crude viral extracts to investigate their anti-cancer properties. However, these early experiments were largely unsuccessful. Eventually, the crude viral extracts were replaced with purified preparations of naturally occurring viruses that were known to have oncolytic effects, such as adenovirus, Newcastle disease virus, reovirus, and herpes simplex virus (HSV). Although the viral isolates were purified, their effectiveness in clinical settings remained limited. In particular, patient immune responses often neutralised the viruses, and any anti-tumour effects were short-lived.
The advent of recombinant DNA technology in the 1990s provided researchers with a new range of tools to genetically modify viruses to enhance selectivity and potency. This sparked renewed optimism that OVs could be modified to make them effective in the clinic.
Even with this renewed interest, regulatory approvals for OVs have been scarce. In 2005, the engineered adenovirus Oncorine (Shanghai Sunway Biotech) was approved in China for advanced head and neck cancer. A decade later, the engineered HSV1 Talimogene laherparepvec (T-VEC) (Amgen Inc), was approved in the US and Europe for melanoma and remains the only OV approved for use in the West. More recently, the engineered HSV1 Teserpaturev (Daiichi Sankyo) was approved in Japan in 2021 for malignant glioma.
Despite this meagre track record, numerous OV candidates are currently in clinical trials for a range of cancers. For example, the unmodified human reovirus isolate Pelareorep (Oncolytics Biotech, CA) is being tested for malignant glioma and metastatic breast cancer, while Pexastimogene devacirepvec (Sillajen, KR), an attenuated vaccinia virus with a GM-CSF payload, is under investigation for kidney, liver, and skin cancers. Other promising candidates include the engineered adenovirus Tasadenoturev (DNAtrix, US) for recurrent glioblastoma, MVR-T3011 (ImmVira, CN) for head and neck squamous cell cancer,and and the replication-competent HSV-1 CAN-3110 (Candel Therapeutics) for recurrent high-grade gliomas.
A significant milestone was achieved in the OVT field in 2024, when Vusolimogene oderparepvec (Replimune, US), an HSV1 with GM-CSF and GALV-GP R payloads, was accepted by the FDA for a Biologics License Application (BLA) and priority review for the treatment of advanced melanoma. This has provided encouragement to the field that further regulatory approvals may be at least on the horizon.
Dual Mechanism of Action
During the early research on OVs, researchers believed that the primary mechanism of action was direct oncolysis, in which the OV selectively replicates in cancer cells and causes them to die. Consequently, early development of OVs focused on engineering the viruses to selectively infect and replicate in tumour cells.
However, researchers later noticed increased immune cell infiltration into tumours that had been treated with OVs. This suggested that OV infection could also stimulate anti-tumour immune responses.
These findings led to the understanding that OVs work through a dual mechanism of action: (1) direct lysis of cancer cells and (2) stimulation of anti-tumour immune responses through the release of tumour-associated antigens and activation of immune pathways. This dual mechanism has shifted the focus of OVT research towards enhancing not just the direct killing of cancer cells by oncolysis, but also their ability to promote immune responses against cancer cells.
Genetic Engineering and Payload Design
Current OVT research has focussed on genetically engineering OVs to carry transgene payloads that enhance one or both arms of their anti-cancer effect.
To improve direct oncolysis, the tumour specificity of viral replication can be increased through engineering OVs with tumour-specific promoters or deleting virulence genes that support replication in normal cells. The spread of an OV through a tumour can be enhanced by introducing sequences encoding fusogenic proteins or modified envelope glycoproteins. The OV’s ability to destroy cancer cells can also be improved by engineering the OVs to express payloads such as pro-apoptotic proteins or anti-angiogenic factors.
To stimulate anti-tumour immunity, OVs may be engineered to express molecules that increase immunogenic cell death, such as pro-inflammatory cytokines. Other payloads, including checkpoint inhibitors or chemokines, help to overcome the immunosuppressive tumour microenvironment. Immune stimulatory molecules like GM-CSF, CD40L, or TLR ligands may also be expressed to directly activate the patient's immune system.
Immune stimulation by OVs may be useful in turning immunologically “cold” tumours into “hot” tumours. This may help to make the tumours more sensitive to other treatment with other immune-modulatory therapeutics, such as immune checkpoint inhibitors (ICIs). Consequently, the use of OVs in combination with other cancer therapies is an area of intense research.
Challenges and Future Directions
Despite their potential, challenges remain to the widespread adoption of OVs. The intratumoural administration route used by many OVTs to date significantly limits their clinical application and the development of OVTs that can be administered systemically would be a significant achievement.
Other challenges include achieving sufficient potency and selectivity to target cancer cells while sparing normal tissues, overcoming rapid neutralisation by the host immune system, and addressing immunosuppressive conditions within the tumour microenvironment.
The manufacture of OVs at clinical-grade quality and required scale presents further obstacles.
Nonetheless, advancements in genetic engineering, synthetic biology, and immunotherapy are helping to overcome these challenges. In particular, the ability to customise OVs and their payloads and the development of effective delivery and targeting systems is paving the way for the development of next-generation OVs with the potential to make a clinical impact.
Protecting next-generation OVs with IP can be challenging due to the difficulty of distinguishing them from previous generations. Patents may for example focus on the tumour-specific promoters, modified viral envelope proteins, targeting molecules, and/or delivery systems that define the next-generation OVs, as well as their combinations with other therapeutic agents. To support the development and commercialisation of OVs, creative patent strategies that provide a strong shield of protection will likely be essential.
A Promising Future for Oncolytic Virotherapy
Oncolytic viruses are poised to play an increasingly important role in cancer treatment. With multiple OVs in advanced clinical trials and new approvals anticipated, OVT is gradually fulfilling its promise as a revolutionary cancer therapy. As researchers continue to innovate and address existing challenges, OVT could provide new hope for patients with hard-to-treat malignancies, potentially transforming oncotherapy in the coming decades.
