Oncolytic Viruses: Viruses as Cancer Killers

The fight against cancer is a relentless one, and scientists are tirelessly working on seeking innovative and potent solutions to its challenges. One of the most exciting recent advancements on this front has been Oncolytic Viruses (OVs)—a unique and ingenious class of viruses that have been remodeled to specifically target, infect, replicate within, and ultimately destroy cancer cells, while leaving healthy cells unharmed¹.

The dual nature of these viruses is somewhat evident from their etymology: “onco” meaning cancer, and “lytic”, describing the process of breaking open of cells. More so, OVs do not just directly kill cells; they serve as potent immune stimulators, leveraging the body’s own defense system to launch a systemic attack against cancer². This dual mechanism positions itself at the helm of modern cancer immunotherapy.

A historical perspective

The concept of using viruses to fight cancer dates back as far as the late 19th and early 20th centuries, when doctors observed that in some cancer patients with viral infections, tumors regressed spontaneously³. These early observations paved the way for “virotherapy,” a broader concept that uses bacteriophages in phage therapy for bacterial infections, whereby viruses are similarly leveraged for their lytic capabilities. However, this concept has evolved further with the recent advent of sophisticated genetic engineering tools, allowing scientists to precisely modify naturally occurring viruses into highly effective, targeted, and safer therapeutic agents.

How oncolytic viruses work

The potency of oncolytic viruses lies in their remarkable twofold attack on cancer:

Selective cancer cell infection and lysis

Oncolytic viruses can either naturally possess a preference for cancer cells or can be specifically engineered to do so⁴. This selectivity often stems from inherent defects in the antiviral defense pathways of cancer cells, or their overexpression of certain cell surface receptors that viruses exploit. For instance, many cancer cells have impaired interferon responses that make them vulnerable to viral replication where healthy cells would typically fight off infection⁵.

Modern OVs are often genetically modified to enhance this tumor-specific targeting property, by deleting viral genes essential for replication in normal cells but not in cancer cells, or by inserting genes that are only activated within the tumor microenvironment^{6, 4}.

Once inside a cancer cell, the virus replicates rapidly, overwhelming the cell’s internal machinery. This unchecked replication causes the cancer cell to burst open by a process called lysis, releasing a fresh batch of new virus particles⁷. These new virions then create a self-amplifying cycle of destruction that proliferates throughout the tumor mass, infecting nearby cancer cells.

Immune system activation

The direct killing of cancer cells by OVs is only half the story, and not even the most critical part. As the cancer cells undergo lysis, they release “danger signals” and tumor-specific antigens⁷. These antigens are essentially molecular fingerprints unique to the cancer cells or highly abundant on them.

These released tumor antigens and viral antigens are then “picked up” by specialized immune cells known as antigen-presenting cells (APCs), such as dendritic cells⁸. APCs act as vital messengers, traveling to the body’s lymph nodes, where they “present” these captured antigens to T-cells⁹. This crucial interaction activates a powerful anti-tumor T-cell response.

These newly activated T-cells then travel throughout the body, specifically targeting and destroying cancer cells, not only in the directly injected tumor but also, remarkably, in distant metastatic sites that were never directly infected by the virus. This phenomenon is known as the “bystander effect” or, when affecting distant tumors, the “abscopal effect”¹⁰.

Furthermore, OVs can be engineered to carry and express additional immune-stimulating molecules, such as cytokines (eg, GM-CSF), directly within the tumor¹¹. This helps to recruit more immune cells, turning “cold” (immune-desert) tumors, which are often resistant to other immunotherapies – into “hot” (immune-inflamed) tumors that are more likely to mount an immune attack¹².

Key oncolytic virus types

Several variants of viruses are now being explored and engineered for oncolytic virotherapy, with some already approved for clinical use:

• Herpes simplex virus (HSV): It is a DNA virus with a relatively large genome that can be easily engineered. Talimogene laherparepvec (T-VEC or Imlygic®), a modified HSV, was the first FDA-approved oncolytic virus in the US in 2015 for advanced melanoma. It’s engineered to replicate preferentially in cancer cells and expresses GM-CSF to boost anti-tumor immunity¹¹.
• Adenovirus: Another DNA virus, known to cause the common cold. H101 (Oncorine®), an engineered adenovirus, was approved in China in 2005 for head and neck cancer¹³.
• Vaccinia virus: A robust DNA poxvirus with a large genome, making it suitable for carrying multiple therapeutic genes, and capable of systemic delivery¹⁴.
• Reovirus: It is an RNA virus that naturally exhibits oncolytic properties in certain cancers, particularly those with activated Ras pathways¹⁵.
• Measles virus: Engineered versions of this RNA virus derived from the measles vaccine strain have shown promise in conditions like multiple myeloma¹⁶.
• Poliovirus: A modified poliovirus (PVSRIPO) is currently under investigation for its potential in treating glioblastoma, an aggressive brain cancer¹⁷.

The promise and the drawbacks

Oncolytic viruses offer several compelling advantages in the fight against cancer.

• Their property of tumor selectivity minimizes harm to healthy tissues, differentiating them from chemotherapy which acts on a broad range of tissues¹⁸.
• Their dual mechanism of action—direct oncolysis combined with potent immune stimulation—provides a formidable combination of attack⁴.
• The self-amplifying nature of viral replication within the tumor allows the treatment to spread and intensify within the tumor mass and potentially to distant sites as well¹⁹.
• OVs can also be instrumental in overcoming immunosuppression within the tumor microenvironment, transforming immune-resistant tumors into targets for immune attack²⁰.
• Furthermore, their synergy with other cancer therapies opens doors for highly effective combination therapies²¹.

However, the journey of oncolytic viruses is not without its share of challenges.

• Host anti-viral immunity poses a significant hurdle in this fight; pre-existing antibodies or a rapid immune response by the patient can clear the virus before it can effectively reach and replicate within tumors²².
• Efficient delivery to tumors, especially for systemic (intravenous) administration to target metastases, remains difficult due to rapid clearance by organs like the liver and spleen²³.
• Tumor heterogeneity is a cause of concern; whereby different parts of a tumor or different metastatic sites might respond differently to the virus²⁴.
• Some of the potential risks include flu-like symptoms, localized inflammation, and, in rare cases, unwanted viral shedding or replication in healthy tissues^25-27.
• On top of it, the manufacturing and cost of production of live viruses under stringent Good Manufacturing Practice (GMP) conditions are complex, and the development of reliable biomarkers to predict which patients will benefit most is still in its nascency^{28, 29}.

Engineering the future of virotherapy

The field of oncolytic virotherapy is rapidly advancing. A major area of focus involves enhanced engineering of OVs to “arm” them with additional therapeutic genes that express powerful anti-cancer agents, immune-stimulating molecules, or even antibodies^{1, 30}. This enables direct and more effective delivery of these genes to the tumor, enhancing treatment efficacy.

Researchers are also focused on improving viral targeting and “stealth” mechanisms, perhaps by modifying viral capsids or encapsulating viruses within carrier cells (like mesenchymal stem cells) to protect them from host immunity and guide them precisely to tumor sites^{31, 32}. This often involves sophisticated nanomedicine approaches, such as encapsulating oncolytic viruses within specialized nanoparticles. These nanocarriers are designed to overcome some of the delivery challenges including systemic administration, evading host immune responses, and enhancing specific cell binding³³. This ensures that these viruses reach and infect tumors effectively. Achieving systemic delivery to all metastatic sites remains a chief objective for these advanced delivery methods.

These novel engineering strategies are rigorously tested and standardized using sophisticated disease models, which serve as a bridge between initial design and clinical translation³⁴.

Combination therapies are proving to be particularly fruitful, especially the synergistic coupling of OVs with ICIs, as OVs can make tumors highly immunogenic, augmenting the effects of ICIs³⁵. Their combination with conventional treatments like chemotherapy and radiation also seems promising^{36, 37}.

The possibility of personalized virotherapy, that is, tailoring the OV approach based on an individual patient’s unique tumor characteristics and immune profile, is gaining momentum³⁸. Development of novel virus platforms with distinct biological advantages forms another critical area of investigation³⁹.

Conclusion

Oncolytic viruses represent a fascinating and promising frontier in cancer therapy. Despite challenges in delivery, host immunity, and manufacturing, ongoing research is rapidly transforming oncolytic virotherapy from an experimental concept to practice. With our deepening understanding of virus-host interactions and cancer biology, OVs are poised to significantly improve outcomes for people worldwide.

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