Timeline: using viruses to fight disease

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.

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).

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.

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.

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.

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.

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."