Oncolytics and the Role of Viruses

In the AI assisted image above, viruses are shown infecting and destroying cancer cells in a groundbreaking oncolytic therapy. This advanced method aims to attack and eliminate tumors. More to follow below.

This is the first of the cancer-related posts for my new (fourth) blog, which I initiated in 2010. My aim is to elevate the complexity of topics typically covered in WebMD-style articles, while ensuring they remain understandable. My interest in cancer was sparked by my father’s diagnosis when I was 26, followed by the illnesses of my late wife in 2005, 2010, and 2012. Finally, I was diagnosed with bladder cancer in January 2023 at the age of 74. You can read about that here. In this section of my new blog, I want to discuss future medical advances in the field of cancer, one of the most promising of which is in viral oncolytics.

The term “oncolytic” is derived from two Greek words: “onco,” referring to a tumor, and “lytic,” which means “to kill,” although lytic is technically an adjective rather than a verb.

A brief history

The first virus discovered was the Tobacco Mosaic Virus, identified in 1892 by a Russian scientist named Dmitri Ivanovsky. The word “virus” was first used in 1898 when Dutch microbiologist Martinus Beijerinck took it from the Latin term for “poison.” Ivanovsky also demonstrated that a virus could replicate itself within a living cell.

In 1904, a leukemia patient developed a curious decrease in leukocyte count after an influenza virus infection. Could there be a relationship between the virus and her cancer? Before long, doctors noticed a correlation between certain viruses and patients with certain types of cancer. For example, one of the earliest cases was reported . . .

“in 1904 by George Dock, a physician at the University of Michigan, was about a female patient with myelogenous leukemia. After a bout of what was assumed to be influenza, her previously enlarged liver and spleen shrank to nearly normal size, and her elevated leukocyte count dropped more than 70-fold. There remission lasted for several months before her death a year and a half later.”

And this was not the first case. Guillaume Dupuytren, a French military physician and occasional surgeon to Napoleon Bonaparte, achieved results similar to those of Dock almost a century earlier. His patient was a woman who had refused surgery for her breast cancer. After eighteen months, the woman was bedridden, the muscles of her body severely wasted, and she was close to death. The patient was feverish, with her tumor “inflamed and gangrenous.” Dupuytren performed an incision and drainage (I&D) and removed a large quantity of foul-smelling fluid. However, to Dupuytren’s surprise:

“Within 8 days, the cancer had regressed to a third of its original size. Within 4 weeks, no clinical symptom of the tumour was present.”

A caveat

There is an important caveat in this cited case. While gangrene can be the consequence of a virus, much more often than not it is caused by a bacteria (Clostridium perfringens). Today, a strain of bacteria (BCG) remains the gold standard in treating bladder cancer (that is, if your physician can locate a supply of BCG). I mention this parenthetically since the focus on this post deals with cancer and viruses and not cancer and bacteria.

One more example

Around 1950, researchers at Memorial Sloan Kettering Cancer Center inoculated mice with astrain of sarcoma with a variant of an encephalitis virus. They noted that at least in some cases, the virus seemed to be drawn to the cancerous tumors in the mice and destroyed them. When virus infected cancer cells were then implanted into healthy mice, the cancerous tumors failed to grow.

So, there are some viruses like the Herpes Simplex virus and the Adenovirus responsible for the common cold, some strains of Measles virus that are natural enemies of cancer cells. Some can even penetrate the cell walls of a cancer cell. These viruses are used as “mules” in some sense to carry proteins and other dangerous cargo that can obliterate cancer cells.

Recombinant DNA

In the 1970’s, barely two decades after the discovery of deoxyribonucleic acid (DNA) by Watson and Crick, researchers were combining DNA from different sources or different species. For an unusual example but interesting one, I’ve blogged about Colossal Biosciences and their attempts to reintroduce extinct species of animals, from wooly mammoths to dire wolves. They begin by extracting whatever scraps of DNA are still available and viable from fossils, hides and so on and “combine” them with the DNA of very similar animals that exist today which are the closest match to the extinct species. This is possible using recombinant DNA techniques which are used in contemporary cancer research.

Unfortunately, we have entered a period in American history where politics is taking preference to scientific research. Research grants to universities have been slashed and scientists fired or muzzled. This will almost certainly have an adverse impact on our ability to fight not only cancer, but other diseases and disorders as well. At the moment, the private sector seems to be unfettered and the best hope for a cure to this and other deadly diseases.

Genetic manipulation to restore extinct species — Researchers at Colossal Biosciences in Dallas, TX use state-of-the-art recombinant DNA techniques and equipment to attempt to repopulate the planet with extinct species of animals. However, they stress that their research is also designed to ensure the survivability of current species from the consequences of a devestating virus or bacteria. Some species such as African cheetahs have almost zero diversity within the breed. Photo courtesy. of Colossal Biosciences. Used with permission.

Current status

Today, with the emergence of CRISPR and its confusing name (clustered regularly interspaced short palindromic repeats), gene editing is easier than ever before. After experimenting with viruses such as the herpes simplex virus (HSV), the adenovirus (AdV), and the vaccinia virus (VV), a very promising oncolytic virus called HSV (T-VEC) was developed and approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of melanoma, commonly referred to as skin cancer. Thus, HSV (T-VEC) became the first licensed oncolytic virus. T-VEC is injected directly into the melanoma lesions, where it causes cancerous cells to rupture. Exactly how it does this is not fully understood.

One significant advantage of recombinant DNA and CRISPR is that cancerous cells can be specifically targeted. In the past, radiation and chemotherapy could only be programmed to kill rapidly growing cells, not just cancer cells. Consequently, killing any cell that has a rapid life cycle (like blood cells and hair cells) simply for the sake of eliminating cancer cells that proliferate rapidly was a sledgehammer approach to treatment, resulting in numerous side effects. Today, doctors can be much more precise and avoid destroying good cells along with the bad.

Here precisely is how it is done:

The use of viruses to attack cancerous tumors boils down to a one-on-one fight between a single virus cell and a single cancer cell, multiplied by thousands or more other pairs of combatants joined in battle. The cancer cell is a living organism; the virus, strictly speaking, is not alive. The challenge for cancer researchers is to “train” or reprogram the virus cell to notice cancer cells and then attack them, instead of targeting the normal, healthy body cells that the virus was originally designed to seek out.

There are certain considerations that make some viruses more ideal than others in fighting cancer. For example, the Herpes Simplex Virus (HSV) has a large genome. A genome is a complete set of DNA for an organism, so that “file” takes up a lot of “space,” for lack of better words. Even though a virus is not alive because it cannot independently reproduce, it can have DNA, and it can also have RNA. Part of the genome involves the genes that produce traits (like pattern baldness in people). A smaller virus can have as few as two genes, while the HSV has 74 to 84 genes. In fact, at least one virus with 1,000 genes has been discovered! The extra “space” to accommodate these genes means that there is more room for researchers to insert foreign or synthesized genes that (1) kill cancer cells while simultaneously (2) sparing healthy cells. Thus, a large genome, like that of the HSV or the human adenovirus, has significant potential. The adenovirus is a favorite among researchers working on oncolytics. This virus causes croup, bronchitis, and most commonly, the common cold. In addition, the side effects of the adenovirus are usually nothing more severe than a runny nose, sore throat, and similar mild symptoms.

You wouldn’t want to use a virus that causes rabies or HIV and inject it into someone to attack their cancer; although you might be successful in removing the cancer threat, the patient could become HIV positive, develop AIDS, or contract COVID-19. What is the point if, either way, the patient dies? Therefore, the basic lethality of a virus is a primary consideration in choosing it, as well as the amount of room it has for additional genes. Another important consideration is the type of cancer cell that needs to be targeted: Can it easily be subdued by a virus? Is there a particular aspect of the cancer cell that is especially vulnerable or defenseless?

Once the virus meets the cancer cell, it invades the malignant cell, uses properties from the cancer cell to reproduce rapidly, and then causes the cancer cell to burst and die. This explosion releases additional viral particles into the tumor, where other cancer cells are subsequently attacked. Also released are special proteins called antigens, which help the body’s immune system better detect and hunt down the remaining cancer cells.

In addition to melanoma, viral oncolytics show promise in treating cancers of the brain. In the case of breast cancer and pancreatic cancer, another viral oncolytic, Pelareorep, is being explored.

How effective is HSV (T-VEC)?

I don’t want to go into the assumptions of a particular study, the different cohorts, constraints and so on. This information can be located by anyone looking for details. Suffice it to say that the monthly peer-reviewed journal Cancer Immunology, Immunotherapy reported on a study that concluded that by itself or in tandem with another approach:

“... intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that the use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.”

Clearly T-VEC is not a silver bullet. But it will save some lives if it cannot save all who have terminal melanoma. Yet, research is continuing and someday it may.

A recent (2025) review of viral oncolytics notes:

"Oncolytic viruses (OVs), a kind of emerging therapeutics for treating tumors, are characterized by high replication efficiency, superior killing effects, and few adverse reactions, which have shown great application prospects in preclinical tumor treatment trials. To overcome the limitations of OV monotherapy, recent studies have found that combination therapy with other anti-tumor therapeutics, especially with immunotherapy, yields promising outcomes in tumor eradication."

TYPE OF CANCER	TREATMENT OPTION	COMMENTS
BLADDER CANCER	Adstiladrin Nadofaragene firadenovec Cretostimogene Grenadenorepvec	“The product is a non-replicating adenoviral vector‑based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.” FDA approved. FDA approved in 2022 for high-risk, non-muscle-invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guérin therapy. Details here. In January 2024, another oncolytic adenoviral construct, cretostimogene grenadenorepvec (CG0070), has been granted breakthrough and fast track status for its FDA approval for treatment of NMIBC following a significant reduction in tumor size.
BRAIN CANCER	GL-ONC1	In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer.
BREAST CANCER	GL-ONC1	Formerly known as GLV-1h68 In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer
COLORECTAL CANCER	RIGVIR	In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer. RIGVIR is approved elsewhere in the world (but not in the U.S.) for colorectal cancer.
GASTRIC CANCER		Upper G/I tract cancers are among the most difficult to treat. Much research remains to be done for cancers of the esophagus, stomach, etc.
HEAD & NECK CANCER	Oncorine	Oncorine, an adenovirus-based OV, is used for the treatment of head and neck cancer. It is approved for use elsewhere in the world but not for use in the U.S.
KIDNEY CANCER		See renal cell carcinoma. While no viral oncolytics are currently approved for RCC, several experimental agents are under investigation, and future therapies may involve combination strategies with existing treatments.
LIVER CANCER	Pexa-Vec	Pexa-Vec has relatively few side effects, but to date has not appeared to show any ability to increase life expectancy of cancer patients. Current efforts involve piggy-backing Pexa-Vec with another drug.
LUNG CANCER		While there are some promising viral oncolytics in development, none have been approved to combat lung cancers.
MELANOMA	T-VEC	Currently the only FDA approved antiviral oncolytic. RIGVIR is approved elsewhere in the world (but not in the U.S.) for melanoma.
OVERIAN CANCER	GL-ONC1	In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer.
PANCREATIC CANCER	GL-ONC1	Pancreatic cancer very difficult to treat (5-year survival rate of only 8.2%). More needs to be done in the area of developing viral oncolytics. In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer.
PROSTATE CANCER	GL-ONC1	In preclinical studies, GL-ONC1 was found to be safe and efficacious against a variety of malignancies including colon cancer, breast cancer, glioma, ovarian cancer, pancreatic cancer and prostate cancer.
RENAL CELL CARCINOMA		While no viral oncolytics are currently approved for RCC, several experimental agents are under investigation, and future therapies may involve combination strategies with existing treatments.
SOFT TISSUE SARCOMA	T-VEC and VG161 are particularly for sarcomas.	While there are currently no FDA-approved oncolytic viruses specifically for soft tissue sarcoma, this area of research is rapidly evolving and holds the potential to significantly impact the treatment of this challenging cancer in the future.