Turning enemies into allies: using viruses to fight cancer

Why are cancers so hard to cure?

Cancers are challenging to cure for several reasons. Firstly, cancer is not a single disease but a collection of more than 100 different types of diseases, each with its unique causes, characteristics, and behaviors. Additionally, some cancer cells can mutate quickly, making them resistant to treatments. With each division and growth, these cells can accumulate more mutations, making them increasingly difficult to manage.

Cancers also often involve a complex interplay with their surrounding environment, including blood vessels, immune cells, and other non-cancerous cells. This interaction can make it difficult for treatments to specifically target cancer cells without damaging healthy tissue. Additionally, many cancer treatments, such as chemotherapy and radiation, can have significant side effects, limiting their use and effectiveness, especially in people with co-morbidities. Sometimes, these side effects can be so severe that they prevent further treatment or severely reduce a patient's quality of life.

Detecting cancer early is vital for effective treatment, too. Still, some cancers may be hard to diagnose in their early stages since they may not display any visible symptoms or be situated in an area easy to image. By the time they are detected, they may have already spread, making them more difficult to treat. Additionally, a single tumor may have various subpopulations of cancer cells with distinct genetic and molecular profiles that respond differently to treatment. As a result, treatment may eliminate some cancer cells while others continue to grow.

Despite these challenges, progress is being made in cancer research, and new treatments are continually being developed. Advances in immunotherapy, targeted therapies, and personalized medicine are all promising avenues for future cancer treatments. One such treatment is using "nature's Trojan Horses;" viruses.

How can viruses be used to fight cancer?

And viruses can indeed be thought of as "Trojan Horses" of a kind. Viruses have evolved strategies to "disguise" themselves or hijack cellular machinery to reproduce and spread within the host organism. This can make them difficult to recognize and eliminate, allowing them to spread infections and diseases.

Since they are so good at attacking cells, researchers have been exploring ways to harness the "Trojan Horse-like" properties of certain viruses to treat diseases, such as using modified viruses to deliver therapeutic genes to cells in gene therapy or using oncolytic viruses to target and kill cancer cells selectively. But how?

Certain viruses have been implicated in the development of specific cancers, such as the hepatitis B virus (HBV) in liver cancer and the human papillomavirus (HPV) in cervical, head, and neck cancers. While HPV and HBV have previously been used to create "cancer vaccines" from these viruses, they have not yet been modified to help combat other forms of cancer. But some viruses, it has been found, can target and infect cancer cells while leaving "normal" cells alone. Called oncolytic viruses, their recognition and use in cancer-fighting may bring us one crucial step closer to banishing cancer for good.

Cancer Research Institute (CRI) explains that oncolytic viruses have been used to target and attack pre-existing tumors. Cancer cells tend to have impaired antiviral defenses, making them susceptible to infection. In addition, some natural viruses can be engineered to give them cancer-fighting properties. To this end, oncolytic viruses can be used to cause cancer cells to "burst," killing them and releasing cancer antigens, which can stimulate immune responses to eliminate any remaining tumor cells. In 2015, the FDA approved the first oncolytic virus immunotherapy for cancer treatment: T-VEC for melanoma. T-VEC, a modified herpes simplex virus (HSV), infects tumor cells and promotes their destruction.

All very interesting, but you might ask, are such viruses safe for the patient's non-cancerous cells? As far as we can tell, they appear to be. Since the viruses attack cancer cells specifically, they appear to leave the rest of the body alone. However, they are not without their side effects.

Side effects of oncolytic virus therapy may vary according to the type of virus, location, type of cancer, and a patient's overall health. Common side effects of T-VEC include chills, fatigue, flu-like symptoms, injection site pain, nausea, and fever. In 2018, CRI investigator John C. Bell revealed that treating triple-negative breast cancer patients (where the cancer cells don’t have estrogen or progesterone receptors and produce very little or none of the HER2 protein) with oncolytic virus therapy before surgery increased their likelihood of responding to checkpoint immunotherapy. CRI is also funding a phase I/II clinical trial for advanced appendiceal (cancer of the appendix), colorectal (cancer of the colon and rectum), and ovarian (cancer of the ovaries) cancer, combining an oncolytic virus and a checkpoint inhibitor.

Various oncolytic virus platforms are being evaluated in clinical trials, including adenovirus, herpes simplex virus, Maraba virus, measles, Newcastle Disease Virus, picornavirus, reovirus, vaccinia virus, and vesicular stomatitis virus. New platforms and approaches are continuously being developed and investigated. Patients should consult a Clinical Trial Finder service to determine eligibility for an immunotherapy clinical trial.

What examples are there of cancer-killing viruses?

We've already mentioned a few above, but another promising treatment involves using the poxvirus.

Poxvirus is a family of large, complex, double-stranded DNA viruses that infect humans and animals. The poxvirus family comprises various genera, including Orthopoxvirus, Parapoxvirus, Avipoxvirus, and Leporipoxvirus. Poxviruses are unique in that they replicate within the cytoplasm of infected cells, unlike most DNA viruses, which replicate within the nucleus.

Regarding cancer treatment, a team of researchers at The City of Hope recently conducted initial trials of a modified poxvirus to target advanced solid tumors. Like oncolytic viruses, the altered virus was designed to enter the host cell, replicate, and subsequently rupture the host cell, releasing thousands of new viral particles. These particles attach to cancer cells, signaling the host's immune system to target the cancerous cells.

The treatment employed in this trial was developed by Australian company Imugene and termed CF-33-hNIS, or Vaxinia. According to a press release, the drug has effectively reduced colon, lung, breast, ovarian, and pancreatic tumors in lab tests and animal models. The hNIS in the drug's name refers to the human Sodium Iodide transporter, a protein the researchers used to track viral replication and cancer cell damage by employing radioactive iodine, as reported by Science Alert.

The Phase 1 trial aims to establish the drug's safety and will involve 100 volunteers across ten sites in the U.S. and Australia. These volunteers are cancer patients with metastatic or advanced solid tumors who have undergone at least two prior lines of cancer treatments. Vaxinia, the experimental drug, will be injected either intravenously or directly into the tumors, as stated in the press release. Once the drug's safety is confirmed, several participants will also receive pembrolizumab, an immunotherapy known to enhance the immune system's ability to combat tumors.

Interestingly, apart from cancer treatment, poxviruses have also been studied for their potential use in gene therapy and as vaccine vectors for other infectious diseases, owing to their ability to carry large amounts of foreign genetic material and stimulate strong immune responses.

Another interesting "cancer-killing" virus is a modified version of herpes. A genetically modified herpes virus, RP2, has demonstrated potential in treating advanced cancers, according to a report by the Institute of Cancer Research in London. In early trials, RP2 killed cancer cells in 25% of patients with advanced and complicated cancers. The engineered virus is injected into tumors, which multiplies inside cancer cells, causing them to burst, and also blocks a protein called CTLA-4, boosting the immune system's ability to kill cancer cells. Three of nine patients treated with RP2 experienced tumor shrinkage, and one became cancer-free five months after starting treatment.

Our bodies' ancient battles with viruses could also be used to "unlock" dormant cancer-defeating abilities already present within us. Endogenous retroviruses (ERVs) are ancient viral relics present in the human genome that may be crucial in fighting lung cancer. These viral DNA remnants may account for nearly 5% of our genome and are mainly dormant. However, some may be reactivated by stimuli, including viral infection.

This ERV activation has been associated with some cancers and possibly also with autoimmune and neurodegenerative diseases. However, ERV activation can trigger an immune response. ERV-mediated inflammation is being explored as a way to activate and trigger an immune response from B cells, known for producing antibodies against infections, and to sensitize tumors to immunotherapy. 

Research showed that antibodies targeting ERVs correlated with longer survival in mice with lung cancer during immunotherapy, potentially paving the way for developing a cancer treatment vaccine to enhance antibody production and improve immunotherapy outcomes.

And that is your lot for today.

If research into using viruses to fight and defeat cancer proves viable, it would be the epitome of getting two enemies to fight one another. The poetic justice of this aside, if such treatments prove to be as effective as claimed by researchers, we could be about to enter a new age of cancer treatment and potential cure.

But let's not get too ahead of ourselves just yet.