Oncolytic Viral Therapy: A promising option for Cancer Treatment

Cancer is a word that fills the thoughts of people with fear. It is a devastating disease and has made so many people lose the lives of their loved ones who were a victim of this disease.

Cancer refers to a group of diseases resulting from the uncontrolled growth of cells in human body. These cells are abnormal cells and form a mass called as tumor. These cells have the potential to spread to other parts of body.

According to WHO, 10 million deaths were reported in patients that were a victim of cancer in year 2020. As it is one of the diseases which are leading cause of death, scientists and doctors are actively working in field of oncology and trying to develop effective remedies to make it just a memory. To date, there are numerous breakthroughs in cancer treatment research including surgery, chemotherapy, radiotherapy, and immunotherapy. Virotherapy i.e., treating cancer through viruses, is a type of immunotherapy.

Can viruses be used to treat cancer?

While talking about viruses, everyone around the globe now knows about these deadly beings, due to a virus arrived on the scene that caused the COVID-19 pandemic which has disturbed the life of almost every person in the world and has taken millions of lives during past one and a half year.

Viruses are infectious invaders which normally infect our healthy cells, increase copies of themselves inside our cells and subsequently infect surrounding cells. In this way, they cause diseases.

The question that arises is, whether or not, the deadly beings as viruses be used to cure a life-threatening disease like cancer? The answer lies in the explanation that there is a certain class of viruses which have a quite unusual biological characteristic of being able to grow very efficiently in tumor cells and not growing at all or hardly growing in normal cells. These viruses that target and infect cancer cells specifically and eventually destroy them are called as oncolytic viruses (OVs).

Where did the idea of oncolytic viral therapy come from?

Around the turn of 19^th century, there were reports of some patients which indicated that their cancers regressed and there was a temporary tumor remission after those patients developed natural viral infections. There was a 42-year-old female patient suffering from myelogenous leukemia. She underwent tumor remission after she contracted an influenza infection.

These observations led to the origination of a notion in 20^th century that tumors can be eradicated with help of viruses. There was testing of several live viruses in both experimental and human settings in 1950s and 1960s for their antitumor activity.

Since then, many scientists directed their energies towards the development of potential oncolytic viral therapeutics for cancer treatment and their efforts never stopped. In the recent years, oncolytic viral therapy has emerged as a formidable treatment option for cancer. Currently, there are many oncolytic viruses and several weakened viruses that have shown promising activity in the elimination of tumor cells in many cancer patients, and some are even available commercially.

Oncolytic viruses targeting tumor cells

There are 2 basic mechanisms by which oncolytic virotherapy works:

• The oncolytic virus enters the tumor cell and causes the tumor cell to burst when it replicates itself inside the cell.
• When the tumor cell bursts, the small pieces of that cell, the telltale markers which are referred to as tumor antigens (TAs) are released in the body. TAs are recognized by receptors on the immune cells i.e., tumor infiltrating cells  (TICs) which get activated.

Also, there are certain chemicals released known as cytokines which further alert the immune system. These cytokines along with other immune cells generate a stronger anti-tumor response in the body against cancer.

Oncolytic viruses preferentially infect cancer cells and not the normal cells. This phenomenon can be explained by a number of  gain-of-function and loss-of-function mutations that occur in cancer cells. The growth of normal cells in our body is regulated and controlled. While the genetic mutations give the cancer cells a growth enhancing attribute , at the same time the important components for defending the cell against infections are lost. In this way, the cells having weak antiviral defenses and become a fertile ground for the replication of viruses. The cancer cells also have more receptors on their surfaces as compared to normal cells to which viruses can attach and enter the cell. Furthermore, viruses can also be genetically engineered to target only tumor cells.

The genetic manipulation of viruses can be done for various purposes like

• For weaking viral pathogenicity to develop oncolytic virus from a pathogenic one
• For enhancing the target selectivity of oncolytic virus
• Inserting the therapeutic genes in viral genome

All in all, use of genetic engineering can be done to enhance the treatment effect of oncolytic virus to eliminate tumors more effectively.

Commercially available oncolytic viruses

Treatment of cancer with viruses is not just a theory or a hypothesis but many scientists have been successful in putting this therapy in practical use. Undermentioned are the 3 OVs which are available commercially.

• RIGVIR^® is an Enteric Cytopathogenic Human Orphan type 7 (ECHO-7) virus belonging to family of picornaviruses. It is not modified genetically and is the first ever  OV to gain approval in the world. It was approved in Latvia in 2004 for the treatment of melanoma and as of now also approved in Georgia, Armenia, and Uzbekistan. It is safe, effective and have not any serious side effects. Since 2011 to 2019, rigvir has treated over 70% of the melanoma patients in Latvia

• Oncorine (H101), developed byShanghai Sunway Biotech Co. Ltd, is the world’s first recombinant oncolytic virus to get regulatory approval in China by Chinese State Food and Drug Administration in 2005. It is a genetically modified adenovirus used for the treatment of patients with late-stage refractory nasopharyngeal cancer along with chemotherapy.

• IMLYGIC^TM (T-VEC), talimogene laherparepvec, is the first OV immunotherapy approved by US Food and Drug Administration (FDA) in 2015 for local treatment of unresectable cutaneous, subcutaneous and nodal lesions in patients with melanoma recurrent after initial surgery and also got approved later in EU for treatment of advanced cutaneous melanoma too. IMLYGIC is a genetically modified Herpes Simplex Type 1 virus (HSV1) and is injected directly into tumors. HSV1 is modified to produce an immunostimulatory protein granulocyte colony stimulating factor (GM-CSF) as it replicates itself in tumor cells.

Apart from these three, there are numerous OVs that are in the process of clinical development and  a  lot of them are already in phase I/II clinical trials. But despite a lot of advancements in cancer research, a major barrier to oncolytic viral therapy, is the presence of neutralizing antiviral antibodies in vaccinated individuals. Strategies are being explored to overcome this problem such as using cell carriers for OV targeted delivery in patients. As for now, OVs are increasingly being combined with other anticancer chemotherapeutic agents for enhancing the responses. But the pace at which the scientists are working and overcoming the shortcomings as observed in the clinical trials and maintaining the benefits of OVs, there is an expectation to see OVs to be used  as monotherapies for combatting cancer in near future.