Oncolytic virus therapies seek to exploit the limited antiviral defenses of cancer cells. Once infected with these viruses, cancer cells eventually burst and release numerous molecules into the tumor microenvironment, many of which stimulate immune cells. For this reason, oncolytic viruses are typically considered to be immunotherapies. Owing to their unique mechanism of action, they have real potential to enhance the efficacy of other cancer treatments. To date, however, only four oncolytic virus therapies have been approved around the world, largely due to a range of preclinical and clinical challenges. Fortunately, advances in viral capsid engineering and delivery technologies are leading to more successes in the clinic and increased hope for the potential of this novel approach to cancer treatment.
Why Viruses Might Make Effective Anticancer Therapies
Cancer cells have strong defenses and few weaknesses, making them difficult to fully eradicate once they have established a foothold. They are very good at evading the host’s immune system by expressing molecules that inhibit the activity of important immune cells.1
Oncolytic virus therapies seek to exploit one of the few weaknesses of cancer cells ― their limited antiviral defenses. Oncolytic viruses infect cancer cells and cause their death and rupture, which results in the release of cancer antigens that stimulate immune cells to attack noninfected cells in the tumor microenvironment.2
It has been observed for nearly a century and a half that, following viral infections, cancer patients often go into temporary remission.3 However, it wasn’t until capabilities in genetic engineering advanced sufficiently that the concept of anticancer agents based on viruses could be really explored. Obviously, wild-type viruses can be harmful to patients.4 The first clinical trials often used highly weakened viruses that exhibited insufficient activity.5
With technology available today, viruses can be engineered not only to target cancer cells while avoiding entering healthy cells but also to carry genetic payloads that cause the expression of other anticancer agents that can increase immune cell effectiveness.6
Oncolytic viruses are also attractive as cancer therapies because of their tolerable safety profiles and completely different mechanism of action compared with other anticancer treatments.7 Because they not only directly kill cancer cells but activate the immune system, they are generally considered immunotherapies.
Both single-stranded (ss) and double-stranded (ds) DNA- and RNA-based viruses are being investigated as cancer therapies, although ssRNA and dsDNA predominate.7 Commonly used dsDNA viruses include adenovirus, vaccinia virus, herpesvirus, with parvovirus the only widely explored ssDNA virus. Both positive-sense (coxsackievirus, Seneca Valley virus, poliovirus) and negative-sense (measles virus, Newcastle Disease virus, vesicular stomatitis virus) ssRNA viruses are used, with reovirus being the main dsRNA virus under investigation.
Cancer cell death is achieved via several mechanisms, including apoptosis, necrosis/necroptosis, pyroptosis, and autophagy.8 Following cell lysis, oncolytic viruses can influence the number of immune cells (macrophages, natural killer cells, dendritic cells, T cells, and neutrophils) entering the tumor microenvironment and reduce immune-suppressing agents and molecules.9 The overall result is conversion of the tumor microenvironment from “cold” to “hot.”8
Current State of the Oncolytic Virus Therapy Market
The first oncolytic viral therapy (Rigvir) was approved in Latvia in 2004 for the treatment of melanoma (butwithdrawn from the market in 2019). Since then, three others have received marketing authorization: Oncorine in China in 2006 for the treatment of squamous cell cancer of head and neck or esophagus, Imlygic (Talimogene laherparepvec, T-VEC, Amgen) in the United States in 2015 for the treatment of certain melanoma patients, and Delytact (teserpaturev) in Japan in 2021 for the treatment of residual or recurrent glioblastoma.8
Currently, the size of the global market for oncolytic viral therapies is estimated to be expanding from $20.1 million in 2023 at a compound annual growth rate of 26.9% through 2032.110
In 2022, there were over 300 clinical trials involving oncolytic virus therapies for treatment of many types of cancer (breast, bladder, brain, pancreatic, ovarian, lung, melanoma, and many more), close to 70% of which were phase I or I/II studies.6 While the majority of oncolytic viral therapies leverage DNA-based viruses,10 some clinical candidates have been engineered using RNA-based viruses. Leading platforms include adenovirus, herpes simplex virus, vaccinia virus, vesicular stomatitis virus, maraba virus, measles virus, Newcastle disease virus, maraba virus, picornavirus, and reovirus, but development of therapeutic oncolytic viruses continues apace, including the investigation of a growing range of other virus families.2
Other selected candidates advancing through the clinical include cretostimogene grenadenorepvec, an adenovirus from CG Oncology for bladder cancer;11 CAN-3110, an oncolytic herpes virus being developed by researchers at Brigham and Women’s Hospital for glioblastoma;12 CF33-hNIS (Vaxinia) from City of Hope and Imugene Ltd. for solid tumors;13 telomelysin from Oncolysis Biopharma for refractory gastroesophageal adenocarcinoma;14 and vusolimogene oderparepvec from Replimune for advanced melanoma (in combination with nivolumab).15 Additionally, Replimune submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration in late November 2024.
Careful Engineering is Required
Most therapeutic oncolytic viruses are engineered via gene-deletion approaches to target cell-surface receptors specific to cancer cells and lack the ability to infect healthy cells. Some also carry genetic payloads (via gene insertion) that cause expression of proteins or other biomolecules that heighten the activity of immune cells.6,17 Examples include viral capsid modification to facilitate transduction and targeting against tumor cells, as well as to improve selective replication and oncolysis.1,8
Virus engineering has also been pursued to stimulate anti-neoplastic immune responses and add genetic payloads that express cytokines, chemokines, proteins, and T cell co-stimulatory molecules to enhance immune responses.1,4 Still other modifications are designed to reduce the harmful nature of the tumor microenvironment (TME) by impacting tumor neovascularization and tumor metabolism.8 For instance, oncolytic viruses have been engineered to carry genes that express ICI antibodies once the viruses have infected the tumor cells.
A Need for Balance
The success of oncolytic virus therapy requires virus replication and immune activation to outpace tumor growth and any antiviral immune responses leading to clearance of the virus.8 It is therefore essential that therapeutic oncolytic viruses are designed to minimize undesired immune responses and maximize those that boost anticancer activity.9 If successfully achieved, oncolytic virotherapy can offer many advantages over conventional immunotherapies, including high specificity and more effective cancer cell killing combined with minimal undesired side effects and a higher capability to avoid drug resistance. Researchers are investigating the use of coatings, nanovesicles, liposomes, polymeric nanoparticles, and other strategies to protect oncolytic viruses from excessive antiviral immune responses.7
Exploring Combinatorial Approaches
Clinical and post-marketing use data for T-VEC and the other approved oncolytic virus drugs supports their high tolerability and safety. Those that are engineered to provide a boosted immune response also show good efficacy as monotherapies. Use of viruses that do not infect human cells and are not pathogenic to people, such as Newcastle disease virus, vesicular stomatitis virus, and Seneca Valley virus, provide the highest level of safety while also having strong, natural tumor-targeting abilities.4,8
However, there is great interest in the use of oncolytic viruses in combination with other treatment modalities, including chemotherapies, immunotherapies (e.g., use in combination with immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies), targeted therapies, and/or radiotherapy.6 A primary driver of this interest is the unique and complementary mechanism of action of oncolytic viruses compared with those of traditional cancer therapies.
T-VEC, for instance, has been shown in a phase II study in combination with Keytruda (Merck) to achieve pathologic complete responses in nearly half of women with early-stage triple-negative breast cancer.18 Indeed, many clinical trials currently underway for oncolytic viruses involve treatment in conjunction with checkpoint inhibitors, including those pursued by academic groups and companies.5 Data suggest that oncolytic viral therapy changes the TME sufficiently to allow immune checkpoint inhibitors to more effectively attack and destroy the cancer cells.3 Similar effects are believed to improve the ability of CAR-T cell therapies to invade the TME.1
There is some debate as to whether engineering oncolytic viruses to express immune-activating antibody-based molecules (e.g., full antibodies, antibody fragments, nanobodies, bispecifics) once they invade cancer cells or combining them with separate immunotherapies offers a better approach.18 Both strategies enable highly specific targeting of tumor cells and the tumor microenvironment.
Using combination therapies reduces the extent of virus engineering required and enables a flexible administration schedule.18 For instance, the antibody-based therapy can be given before, simultaneously, or after oncolytic viral therapy treatment to achieve optimum outcomes. “Armed” oncolytic viruses, however, allow for localized expression, thereby mitigating the systemic toxicity and likelihood of the development of drug resistance with systemically delivered immunotherapies. It is also possible to deliver multiple anticancer agents at one time if they are expressed within the tumor cells, including those that can increase the susceptibility of the TME to attack by immune cells.
Clinical and Preclinical Hurdles
Realizing the significant potential of therapeutic oncolytic viruses requires overcoming numerous challenges to their development at both the preclinical and clinical stages.7 Preclinical models are limited and those that do exist are not standardized and typically have a limited ability to asses and accurately predict in vivo performance in humans.
In the clinical setting, few predictive biomarkers have been identified that can support the selection of not only suitable patients but appropriate tumors/lesions for a given patient.7 Delayed immune responses, meanwhile, make selection of appropriate endpoints difficult. Obtaining evidence justifying specific dosing strategies is another issue, as they must typically be determined empirically and often vary from patient to patient. In addition, because these treatments are live replicating viruses, specialized facilities, protocols, and skilled healthcare workers are required to ensure proper handling and administration and thereby mitigation of biosafety hazards and avoidance of viral shedding and unintended transmission.
For randomized trials, access to appropriate controls for therapies administered intratumorally can also be challenging.7 Indeed, intratumoral administration can be a significant limiting factor for oncolytic viral therapeutics other than those designed to treat skin cancer and other tumors that are easily accessible. Furthermore, in most cases, not all lesions can be treated. Intravenous delivery is preferred, as it is easier to implement and ensures that all lesions are treated but requires overcoming issues with early viral clearance and optimal dosage determination.
Finally, determining when oncolytic virotherapy should be administered can be difficult. While initial studies focused on treatment at the later stages of diseases, evidence is mounting that some oncolytic viruses may be best administered during earlier stages as a first-line treatment.15
Development Efforts Target Systemic Delivery Solutions
To overcome many of these issues, much of the efforts in academia and by startup companies developing therapeutic oncolytic virus products is focused on developing systemic delivery solutions. Intravenous (IV) administration would expand the range of cancers oncolytic viruses could treat, make delivery easier, and enable treatment of metastatic cancers.1 It also eliminates the risks associated with puncturing tumors, including bleeding and undesired metastasis.8 Protecting the viruses from clearance is perhaps the biggest challenging to achieving systemic administration.
Several different approaches are being pursued to address this issue. One involves engineering the viral capsids to reduce their immunogenicity.4 Encapsulation is a more predominant strategy, and includes the use of a wider range of delivery vehicles, such as natural and synthetic biomaterials to different types of cells, including those taken from the patient.4,8
For instance, one research group has shown that carrier cells with innate tumor tropism can achieve more efficient systemic delivery of oncolytic viruses.4 Another group has used intracellular-delivering Salmonella bacteria, which preferentially accumulates in cancer cells, to release oncolytic viruses with a higher therapeutic index than other cellular carriers, such as exosomes, T cells, and mesenchymal stem cells.19
Select companies developing oncolytic virus therapies designed for systemic delivery include Calidi Biotherapeutics (NeuroNova 1, NNV1), IconOVir Bio (IOV-1042), KaliVir Immunotherapeutics (VET3-TGI), and TILT Biotherapeutics (TILT-123).16 Separately, several developers of oncolytic virus therapies have received various accelerated approval designations from the U.S. FDA, including but not limited to CG Oncology for cretostimogene grenadenorepvec, Genelux for Olvi-Vec (olvimulogene nanivacirepvec), Theriva Biologics for VCN-01, and Virogen Biotech for VG161. Many other big pharma and emerging biotech companies are also pursuing the development of oncolytic virus therapies.
References
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Shalhout, SZ, DM Miller, D.M., KS Emerick, et al. “Therapy with oncolytic viruses: progress and challenges.” Nat. Rev. Clin. Oncol. 20: 160–177 (2023).
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Oncolytic Virotherapy Market – Virus Type (Genetically Engineered Oncolytic, Oncolytic Wild-type), Application (Solid Tumors, Melanoma), End user (Hospitals, Specialty Clinics, Cancer Research Institutes) – Global Forecast (2024 – 2032). Global Market Insights, May 2024.
Leslie, Mitch. “Tumor-killing viruses score rare success in late-stage trial.” Science. 382. Dec. 2023.
Chiocca, E. Antonio et al. “Clinical trial links oncolytic immunoactivation to survival in glioblastoma.” Nature. 623: 157—166 (2023). doi: 10.1038/s41586-023-06623-2.
Ryan, Chris and Kyle Doherty. “FDA Grants Orphan Drug Designation to CF33-hNIS for Cholangiocarcinoma.” OncLive. 18 Sep. 2024.
Zamecnik, Adam and Phalguni Deswal. “Immunotherapy insights: Oncolytic viruses struggle to find a spot in a crowded field.” Pharmaceutical-Technology.com. 21 Jul. 2023.
Replimune Receives Breakthrough Therapy Designation for RP1 and Submits RP1 Biologics License Application to the FDA under the Accelerated Approval Pathway. Replimune. 21 Nov. 2024.
Shah-Neville, Willow. “7 oncolytic virus companies you should know about.” Labiotech. 14 Mar. 2024.
Southall, Jennifer R. “Oncolytic virus therapy may boost antitumor response in triple-negative breast cancer.” Healio News. 28 May 2024.
Wan, PK-T, RA Fernandes, and LW Seymour. “Oncolytic viruses and antibodies: are they more successful when delivered separately or when engineered as a single agent?” Journal for ImmunoTherapy of Cancer. 11:e006518 (2023).
Khanduja, Shradha et al. “Intracellular delivery of oncolytic viruses with engineered Salmonella causes viral replication and cell death.” iScience. 27 (2024).