Timeline: using viruses to fight disease
Since the invention of vaccines to treat infections in the 18th century, there have been significant advances in using viruses to fight a range of more complex, non-infectious diseases. Allie Nawrat tracks progress in sourcing and genetically engineering viruses to treat cancers and genetic conditions.
Viruses are an infective agent composed of genetic material that replicate inside the cells of another organism and cause the spread of disease in that organism. Despite their role in causing disease, they have also been found to be highly effective and useful in treating disease.
This concept was first discovered in the late 18th century and informed the discovery of vaccinations to treat both bacteria-based and viral diseases. However, as researchers have extensively studied viruses over the centuries, they have found they can also be used as vectors for gene therapies and can be engineered to target certain cancerous tumours.
Jenner develops the first successful vaccine
In the late 1700s, British doctor Edward Jenner noticed that farmers who had caught cowpox from cattle were not able to catch smallpox, a disease with a high mortality rate at the time.
As a result, Jenner decided to experiment to find out if infecting a patient with cowpox could more safely and effectively immunise them from smallpox than the traditional variolation method that infected them directly with smallpox.
He experimented with his gardener’s son, James, and found, to his relief, that variolating James with smallpox after his recovery from cowpox meant the boy did not develop smallpox.
Using cowpox, rather than smallpox, was a safer approach to developing immunity, because cowpox was a less serious condition.
He repeated this experiment on other human subjects, including his 11-month-old son, and published his research. The terms vaccine and vaccination are derived from the scientific name of cowpox, Variolae vaccinae.
Pasteur attenuates viruses for other diseases
Unlike Jenner who used a virus that was similar, but safer, to confer immunity to smallpox, French microbiologist Louis Pasteur created a vaccination containing a weaker, attenuated version of the original disease-causing bacteria or virus.
Pasteur did this first with anthrax in 1881 using an attenuated form of the bacillus bacteria that caused it, and then with rabies in 1885. Rabies is an often fatal, viral disease that affects the central nervous system; the standard treatment for rabies at the time was cauterisation with a red-hot iron.
Pasteur used a sample of the rabies virus from infected dead rabbits, which was dried for five to ten days, to treat his first patient, nine-year Joseph Meister, who faced almost certain death if not treated; Meister lived until the age of 64 as a result of the success of Pasteur’s vaccination.
Attenuated viruses remain the basis of many vaccinations used routinely globally today; however, they are often not derived from neural tissue due to associated neurological risks.
exploiting viruses’ natural anti-cancer properties
Building on the realisation in the late 1800s that viruses are the cause of some cancers – such as human papillomavirus and cervical cancer – and the observation that occasionally when a cancer patient contracts an infectious disease this would lead to periods of clinical remission, in the mid-1900s researchers began to focus away from surgery and investigate whether viruses could help improve cancer treatment.
According to a 2007 paper published in the journal Molecular Therapy, this move was aided by better scientific understanding of the mechanism and structures of viruses.
Initially researchers focused on finding viruses that naturally targeted tumours, such as the poliovirus, adenovirus, which causes the common cold, and hepatitis B virus. These viruses both directly infect and kill cancer cells, as well as induce anti-tumour immune system responses in the patients.
Unfortunately, success with therapies containing naturally occurring viruses was limited especially in terms of prolonging long-term survival.
Considering viruses to deliver genetic material to cells
In 1970, US scientist Harold Varmus joined the lab of California-based biologist Michael Bishop. Soon after, the pair demonstrated that y-retroviruses can naturally acquire cellular genes. This, combined with viruses’ natural infection mechanism being to introduce genetic material into a host cell, suggested that viruses could act as a delivery system for directly introducing genetic material into the cell.
Further research determined that there were a range of viruses appropriate to act as viral vectors for gene therapies; these include retroviruses, adenoviruses, which cause the common cold, lentiviruses, such as human immunodeficiency virus, and herpes simplex virus type 1 (HSV-1).
Smallpox becomes first disease eliminated through vaccination
At the end of the 1950s, the World Health Organization (WHO) initiated a global eradication programme of smallpox in 1959, making it the first disease to be fought on a global scale; however, the project was only fully implemented in 1966 when the WHO committed $2.4m in annual funding.
This eradication effort was very successful; by 1975 the virus only persisted in South Asia and the Horn of Africa and five years later the WHO certified that smallpox had been globally eradicated.
The vaccination used in the eradication campaign is similar to Jenner’s original. Rather than containing an attenuated virus, the smallpox vaccine contains an active, infectious form of vaccinia, which is immunologically related to cowpox and smallpox.
Smallpox remains to this day the only human disease to be completely eradicated through vaccination. However, the world is on the cusp of achieving this feat with polio, with only 500 cases recorded annually and infections confined to three countries: Afghanistan, Pakistan and Nigeria.
Genetically modifying viruses to create oncolytic virotherapies
Using naturally-occurring viruses to treat cancers began to be largely abandoned in the 1970s. However, as DNA modifying technology developed, it became possible to engineer viruses to improve their ability to target and kill specific cancer cells, as well as induce an immune response; creating what is termed oncolytic virotherapies.
HSV-1 was one of the first to be adapted to selectively target and destroy cancer cells. HSV-1 was an attractive candidate for cancer drugs because its replicative life cycles leads to cell destruction, it has a large genome with many non-essential genes that can be engineered and it remains within the infected cell to prevent disease relapse.
In 1991, researchers from Glasgow-based Institute of Virology deleted the gene ICP34.5 from the HSC1716 strain and showed that doing so helped the virus to kill tumours in tumour culture cell lines.
China approves first oncolytic virotherapy
In 2005, the Chinese State Food and Drug Administration (SFDA) approved the world’ first oncolytic virotherapy, Shanghai Sunway Biotech’s H101. The treatment is an adenovirus, which has had two gene deletions – E1B and E3 – and is indicated for nasopharyngeal cancer, a head and neck cancer common in China.
The H101 virus was acquired by Sunway from Onyx Pharmaceuticals; Onyx’s virotherapy, which only had one gene deletion, according to a 2006 article in the Journal of the National Cancer Institute, had been discontinued in the clinical development stage by Pfizer in 2000 after the pharma giant acquired Onyx’s development partner, Warner-Lambert.
First oncolytic virotherapy approved in the West
BioVex’s Talimogene laherparepvec (T-vec) became in 2015 the first oncology virus immunotherapy approved in the US, Europe and Australia. It is indicated for advanced melanoma lesions that cannot be operated on; it has not proven efficacy in expanding patient survival or preventing metastasis.
T-VEC is a HSV-1 engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF), while two other genes, which shut down cell’s defences and that helps the virus to evade the immune system, were deleted. Clinical studies showed that T-VEC is effective against cancer cells by directly mediating their death and augmenting immune responses.
First viral vector gene therapy approved in the US
In December 2017, Spark Therapeutics’ Luxturna (voretigene neparvovec-rzyl) was approved by the US Food and Drug Administration (FDA). Although it was not the first gene therapy to be available in the US – Novartis’ CAR-T therapy Kymriah pipped it to that title by a few months – Luxturna was the first that uses a viral vector.
Luxturna is approved for an inherited retinal disease (IRD), called Biallelic RPE65 Mutation-associated Retinal Dystrophy, which has no other currently approved treatment options.
Using an adeno-associated virus (AAV) vector that cannot cause disease, the drug delivers a functional copy of RPE65, a retinal pigment epithelium-specific protein, which is mutated in this IRD and will eventually cause blindness, into the cells of the patient.
Ongoing research into use of viruses to treat disease
Researchers and companies are working to expand the number of indications, both in oncology and genetic disorders, which can be effectively treated using virus-based therapeutic approaches.
One example is a recently published report from the University of Surry, which showed that oncolytic coxsackievirus (CVA21), which is a naturally occurring strain of the common cold and shares a human receptor with the adenovirus, was effective in eliminating non-muscle invasive bladder cancer (NMIBC) in 15 patients.
University of Surrey Research Fellow Dr Nicola Annels said: “Oncolytic viruses such as the coxsackievirus could transform the way we treat cancer and could signal a move away from more established treatments such as chemotherapy."