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Wednesday, May 20, 2009 | They’re among humankind’s oldest and most inveterate enemies, but if current efforts prove successful, they could someday be tamed to fight a foe more fearsome still. Today an increasing number of researchers, including one scientist at Salk Institute, are investigating an intriguing possibility: that some viruses could become unlikely allies in the war on cancer.

The idea of using viruses to target and destroy cancer cells, sometimes known as virotherapy, is not in itself a new concept.

As early as 1912 in one case and the 1940s in others, scientists noticed that some cancer patients injected with weakened strains, like those used in vaccines, showed a temporary improvement. At the time, however, scientists lacked the genetic engineering techniques available to modern science, and virotherapy was largely abandoned during the 1950s and 60s. Now some researchers have rekindled interest by crafting new oncolytic viruses, viruses that selectively infect and kill cancer cells, using genetic engineering.

The single greatest advantage might be the lack of toxic side effects. Many cancer therapies not only attack the tumor but damage healthy cells as well. Chemotherapy drugs, for example, often have dose-limiting toxicities, meaning that doctors can only administer so much of the drug because of the toxic effects. The limited dose sometimes permits the more resistant cancer cells to survive, and over time the tumor becomes increasingly resistant.

Virotherapy could overcome this drawback by singling out the tumor cells and sparing the healthy ones. Many oncolytic viruses have achieved remarkable success in the lab and in animal tests, sparking further interest.

Experts stress that virotherapy is unlikely to be a “magic bullet.” The history of cancer research is replete with innovative ideas that haven’t yet come to fruition, and as with other experimental therapies, it’s not yet possible to know how effective virotherapy will prove to be. Nonetheless, many are optimistic that oncolytic viruses will eventually become a valuable addition to the medical arsenal — probably one that would be used in conjunction with other traditional therapies, like chemotherapy or radiotherapy.

“I think it’s probably going to be one of our next major platforms,” says Dr. Tony Reid, director of the UCSD Moore’s Cancer Center Clinical Trials Office.

Reid has been involved with multiple clinical trials in the past that made use of oncolytic viruses, including clinical trials for a genetically altered cold virus that was approved in China in 2005 to treat head and neck tumors. While Reid cautions that these new treatments could take years to develop and pass through clinical trials, he sees them as a promising approach.

Reid’s interest in the subject dates back to his graduate work at Stanford, when he studied cancer treatment using interferons, messenger proteins cells use to warn their neighbors when they are infected by a virus. Reid noticed that cancer cells lack some of the defenses healthy cells have against infection.

“I realized that … the inability to mount an antiviral response was the Achilles’ heel of cancer cells,” he said.

Striking at Cancer’s Weak Spot

Yet finding ways to strike that Achilles’ heel can be a complex task. Both the challenge and the promise of virotherapy stem from the very nature of viruses themselves.

Compared to organisms like plants and animals, viruses are deceptively simple. While human cells contain an estimated 20,000-to-25,000 genes, HIV, for example, contains just nine. The methods viruses use to gain entry vary — some trick cells into admitting them, for instance, while others attach themselves to the cell and “inject” their genes — but once inside, this unwelcome guest hijacks the cell’s natural machinery to replicate itself.

With most viruses, the hapless host cell eventually bursts and dies, scattering a swarm of new viruses, each of which infects other cells in its turn — like an army of mindless clones programmed to carry out a lethal mission.

As an anticancer weapon, viruses have several attractive features. Each infected tumor cell spawns thousands of copies that spread to other tumor cells. The virus can be armed with additional cargo to implant in its targets, like genes to stimulate the immune system. Finally, many cancer cells are especially susceptible to infection. The trick is to genetically alter the virus so that it can no longer infect healthy cells. At that point it can massacre the tumor cells while healthy tissue survives unscathed.

A number of groups are pioneering the use of virotherapy to attack tumors. Researchers at the Mayo Clinic, for example, are working with a genetically altered strain of the measles vaccine virus that targets cancer cells.

“In every single model that we’ve used … we’ve seen significant antitumor activity,” said Dr. Eva Galanis, professor of oncology at the Mayo Clinic.

As an added plus, that virus can cause infected cells to fuse with other tumor cells. “For every one cell infected, we can kill 60 to 100 other cells,” Galanis said. It’s currently in Phase I clinical trials for several different types of tumors, including ovarian cancer.

Biotech companies like BioVex in Massachusetts or Oncolytics Biotech in Canada also have oncolytic viruses undergoing testing. Genelux, an international privately held company headquartered here in San Diego, is working with the vaccinia virus, best known as an immunization for smallpox.

“This virus is capable of delivering anything we attach to it into the tumor,” says Dr. Aladar Szalay, company president and CEO. Genelux has altered the virus to improve it as an anticancer agent and to add a gene that codes for a light-emitting protein; the protein causes infected tumor cells to glow, enabling scientists to track progress. Genelux’s product is still in Phase I clinical trials.

The Tale of One San Diego Researcher

And for one scientist here at the Salk Institute, oncolytic viruses first became an interest during her graduate work at the University of London.

Clodagh O’Shea, an assistant professor in the Molecular and Cellular Biology lab at Salk, heard the director of the University of California, San Francisco’s cancer center do a talk on the new approach while she was working on the immune system.

O’Shea, originally from Ireland, later went on to complete post-doctorate studies at UCSF and has been with Salk since 2007. The diversity of scientific experience in San Diego makes it an excellent place to pursue her research, she said. “This is the advantage of San Diego — and one of the reasons I came here — that there’s such a broad wealth of experience in all of these different areas.”

Cancer is caused by accumulated damage to a cell’s DNA that causes it to divide uncontrollably; instead of performing its normal functions, a cancer cell keeps on dividing and grows rapidly. Some of the changes viruses make in a cell when they infect it are very similar to the changes that cause cells to become cancerous, O’Shea said.

This similarity creates an opportunity for researchers seeking new ways to attack cancer by allowing them to find targets to exploit.

To take one example, when a cell in your body has DNA that’s too badly damaged to be repaired, or when the cell is infected by a virus, a protein called p53 will sometimes cause the cell to commit suicide. This self-destruct process, called apoptosis, is a defense your body uses to prevent viral infections from spreading and stop cells from becoming cancerous.

Most viruses and cancer cells overcome this defense by inactivating p53. A virus will inactivate p53 when it takes over a cell; cancer cells often have a mutation in the gene that codes for p53. If a virus is altered so that it can’t inactivate p53, it will only be able to replicate itself in cells that don’t have p53 — the cancer cells.

“And we think we may be able to do that now,” O’Shea said.

Her work also benefits from recent improvements in genetic engineering technology that could potentially make the process of altering viruses quicker and more efficient. Existing methods of genetically altering viruses can sometimes take 6 months to 12 months to bear fruit, she said, but new techniques could reduce the time necessary. “It’s a really exciting time to be working in this field. We may have the potential to do things that have never been done before,” O’Shea said.

Despite all the apparent advantages to virotherapy, however, there are several hurdles yet to be overcome.

Ironically, the most serious barrier involves your body’s own immune system, which can’t tell oncolytic viruses apart from harmful intruders. The same white blood cells that protect you from disease will mobilize to protect the tumor — and hunt down the anticancer viruses. Yet inciting the body’s immune system could also be beneficial; if a virus could provoke the immune system into recognizing or fighting the cancer cells, the resulting havoc might be very effective. “Would you want to trigger an immune response or suppress it? That’s the thing we don’t know,” O’Shea said. “I still think it’s one of the major questions.”

Some researchers are trying to design viruses to more effectively elude the body’s immune system; others think that temporarily “knocking out” the immune system using drugs is preferable, especially since many cancer patients are being treated with chemotherapy, which usually suppresses the immune system temporarily anyway. The Mayo Clinic, for example, is pursuing both approaches — temporarily knocking out the immune system with chemotherapy drugs and also using “carriers” to shepherd the viruses to where they need to go. Deciding how to evade or exploit the immune system is a crucial question for research in virotherapy.

“It offers us so much control, but it’s not simple,” O’Shea said. Ultimately, while recent advances in genetics and genetic engineering make virotherapy especially promising, researchers agree that further study is needed, and a more complete understanding of the viruses themselves is vital. “People have this misconception that just because it’s small it’s simple. We need to be able to understand them better in order to be able to easily design these things.”

Regardless of the challenges, the goal remains the same: equipping a wily predator to hunt down an insidious prey. If researchers succeed, some of the same viruses that have plagued humans since prehistory could, with the help of genetic engineering, be converted into bio-weapons to save lives. “Cancer is a sophisticated disease,” O’Shea said, “what we may need [to better treat it] is an agent as sophisticated as the disease itself.”

Jonathan Parkinson is a San Diego-based freelance writer. Please contact him directly at jlparkinson1@gmail.com with your thoughts, ideas, personal stories or tips. Or set the tone of the debate with a letter to the editor.

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