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The end of chemotherapy?

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Are we finally in the end-days of chemotherapy? If we are, the toxic kill-or-cure agent will have been toppled by the common cold – and it could all happen within the next few years. By then, the cold virus may well have become the standard treatment to beat a range of cancers, many of which are currently considered untreatable.

Virotherapy – which uses adapted viruses and bacteria to treat cancer and diseases of the central nervous system – has been on the medical radar for more than a century, but it’s suddenly taken center stage.

Just in the past few months, researchers from the UK’s University of Surrey have reported using the common cold virus, coxsackievirus, to treat 15 cases of bladder cancer, and found it can eradicate the tumors in just one week.
The patients were given an infusion of the virus directly into the diseased bladder. The viral infection caused the bladder to become inflamed, and this triggered an immune response that killed the cancer cells.1

“The virus gets into the cancer and replicates, like a little factory of viruses. It heats up the tumor environment and is very specific in targeting the cancer. It had the least toxicity I have seen in years,” said lead researcher Professor Hardev Pandha.2

When Pandha and his team examined tissue samples from the bladders a week after the infusion, they discovered that the virus had not attacked healthy cells – unlike chemotherapy, which kills all living cells – but had infected only the cancerous cells, causing them to rupture and die. The cancer was reduced dramatically in most of the samples, and in one, it had completely disappeared.

“Reduction of tumor burden and increased cancer cell death was observed in all patients and removed all trace of the disease in one patient following just one week of treatment, showing its potential effectiveness. Notably no significant side-effects were observed in any patient,” Pandha declared.

Urine samples from the patients also contained cancer cells that were being “shed,” which suggests the therapy is ongoing and continues to kill cancer cells as they begin to develop.

The virus could become “a universal agent” to treat all cancers within three years, the researchers say. It’s also being trialed on cases of breast, bowel and lung cancers, and as a treatment for a range of skin diseases.

Getting to market
Virotherapy could “transform the way we treat cancer and signal a move away from more established treatments such as chemotherapy,” said Dr Nicola Annels, a research fellow at the university.

Early versions of cancer-fighting oncolytic virotherapy are already on the market. In 2005, China’s drug regulator was the first to approve an oncolytic virus, H101, marketed as Oncorine, which is a genetically modified virus that treats head and neck cancers.

The US Food and Drug Administration followed 10 years later when it approved T-VEC, a modified form of the herpes virus, to treat the skin cancer melanoma. Regulators in Australia and across Europe gave it their assent a year later.

It’s all been a long time coming, ever since the early 1700s, in fact, when physicians noted that cancer went into remission – and sometimes was being completely cured – when patients developed an infection.

Dr William Coley, a New York surgeon, pioneered the use of bacterial vaccinations to treat inoperable cancers until his death in 1936, but then virotherapy took a back seat to newer therapies such as radiotherapy and, after the Second World War, chemotherapy .

The last few years have seen a renaissance in virotherapy research, and although the Surrey researchers have recorded the most significant breakthrough, others have not been far behind. In one research study, the herpes simplex virus, which can cause cold sores and a sore throat, was harnessed to kill neuroendocrine cancer (NEC) cells in laboratory tests.

NEC affects cells in the stomach, bowel and lungs. Surgery to remove the tumor is the usual approach, but researchers from the German Cancer Research Center say virotherapy is a “promising” new way to treat it.3

Colon cancer may also be a target for virotherapy. Researchers at Duke University Medical Center say viruses are a natural delivery mechanism that can target cells, and their focus has been on treating colon cancer, or colorectal carcinoma.4

Measles, not all bad
The measles virus – which the world wants to eradicate – has killed glioblastoma cells, a very aggressive and usually lethal type of brain tumor. Researchers from the University Hospital Tübingen in Germany have tested modified measles viruses on cell lines of glioblastoma in the laboratory and discovered, as the Surrey researchers found, it caused inflammation that eventually killed the cells.5

Doctors at the Mayo Clinic experimented with the measles virus just a few years earlier, using it to treat a patient with end-stage myeloma, a cancer of the blood.

The 49-year-old woman saw the Mayo as a last resort after enduring chemotherapy and two stem cell transplants; by the time of her appointment, she had a golf ball-sized tumor on her head and probably just weeks to live.The Mayo team engineered, or genetically modified, the measles virus strain, and gave the woman a dose that was enough to vaccinate 10 million people.

The response was almost immediate; within five minutes, the doctors say she developed a splitting headache and a temperature of 105°F, before she started vomiting and shaking. The large tumor disappeared inside of 36 hours, and all signs of cancer had disappeared from her body within two weeks.

The virus makes cancer cells join together and explode, explained Mayo Clinic researcher Dr Angela Dispenzieri. It also stimulates the immune system to detect any recurring cancer cells and mop them up.6

“I think we succeeded because we pushed the dose higher than others have pushed it,” said fellow Mayo researcher Dr Stephen Russell. “The amount of virus that’s in the bloodstream really is the driver of how much gets into the tumors.”

Plants too
But it’s not only the common, garden-variety cold and measles viruses that can be employed. Viruses from plants, such as cowpea mosaic virus, and from bacteria – already used in phage therapy – could also be cancer fighters. These viruses act as a delivery system after their capsid – the protein shell that wraps around the virus – has been modified, say researchers at Rice University in Houston.7

And they attack the Achilles’ heel of the cancer cells. As they develop, cancer cells lose their ability to protect themselves from viral infection, explained Grant McFadden at Arizona State University.

“The challenge is picking the right virus, deciding how to arm it and how to deliver it,” he said. With some cancers, an injection can go directly into the tumor, but others are inaccessible or even spread throughout the body.8

In most cases, the infection also induces a fever, and fever seems to be the common factor in many cases of spontaneous remission when cancer mysteriously disappears. Most of the remissions that Coley researched resulted from a bacterial infection, although researchers are showing that viruses can have the same healing effects – and against our most mortal enemy.

Back to bacteria
With the overuse of antibiotics causing the rise of the superbug, phage therapy – which uses specific bacterial viruses to treat infections – has become a possible alternative.

It’s been widely practiced in Russia, Georgia and Poland for 80 years or more, and was us
ed to treat soldiers’ wounds during World War II, but research in the West came to an abrupt stop with the discovery of penicillin.

Researchers have taken a fresh interest and have been testing it on infections such as MRSA, while clinical trials have been examining its effectiveness for otitis, the ear infection. Others have looked at its ability to treat the stomach bug, E. coli.

This year, the US Food and Drug Administration approved the nation’s first clinical trial of phage therapy delivered intravenously.

When cancer just goes away
William Coley was a young surgeon freshly graduated from Harvard when, after failing to save the life of a 17-year-old girl from cancer, he became obsessed with the disease and especially spontaneous remissions, those rare cases when cancer just mysteriously disappears.

But as he researched the medical literature, he realized they weren’t so mysterious; they followed a pattern. The cancer patient had contracted a bacterial infection that induced a high fever, and subsequently, the cancer went away.

There was even a case on his own doorstep in New York. One day in the late 1890s, Coley paid a visit to Fred Stein, whose end-stage sarcoma disappeared after he suffered a bout of erysipelas, a severe bacterial skin infection.

Stein had had the tumor removed several times, but it kept recurring, and surgeons had given up on him, especially after the erysipelas infection. Stein told Coley that the infection caused a raging fever after it had spread over his face and neck – where the cancer was. He suffered a second attack several weeks later, but then his tumor disappeared – and there he was, seven years later, alive and well to tell Coley his story.

Coley went back to Memorial Sloan-Kettering Hospital, as it is now called, and prepared a concoction from the erysipelas bacteria, which he injected directly into a patient’s neck sarcoma. Within an hour, the patient developed chills, pains, nausea and a high fever of 105°F (40°C). The infection lasted 10 days, but by the second day, the tumor started to break down. It had completely disappeared in two weeks.

This was the start of years of clinical research where Coley would try different variations of bacteria, collectively known as MBV (mixed bacterial vaccine) – also called Coley’s Toxins – on a range of cancers.

His overall success rate was around 10 percent for incurable or inoperable cancers, but his work was never accepted by his peers and largely became forgotten when new approaches such as radiotherapy were introduced.

1 Clin Cancer Res, 2019; doi: 10.1158/1078-0432.CCR-18-4022
2 Daily Telegraph, July 4, 2019
3 Neuroendocrinology, 2019 Jun 13; doi: 10.1159/000500159
4 Expert Opin Biol Ther, 2005; 5: 1627-33
5 Mol Ther Oncolytics, 2018; 12: 147-61
6 Mayo Clin Proc, 2014; 789: 926-33
7 Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2019; 11: e1545
8 Live Science, November 18, 2018

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Article Topics: Cancer, oncology, virus
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