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Fighting cancer with virus

The war on cancer goes on and on, and despite limited victories — mainly when tumors are discovered early — the death toll refuses to slacken. One of the more promising innovations uses something seen 100 years ago: Some viruses kill tumors.

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Cell explodes as virus progeny exits.

Viruses commandeer cells, force them to make more virus. When the cell explodes, it dies, releasing thousands of new virus particles.

Nothing in nature rivals the virus for entering a cell, duplicating itself, and then exploding the cell to release thousands of brand-new virus particles. This enter-duplicate-kill-release process relies on biological tools perfected through millions of years of evolution.

And it can be compelling, says Timothy Cripe, chief of hematology and oncology at Nationwide Children’s Hospital in Columbus, Ohio. Cripe, who advocates intensive testing of cancer-fighting viruses, says, “If you look at a virus spreading through a culture dish or animal model after one injection and see the tumor melt away, that’s powerful. It has a lot of promise.”

Outsiders may deem it insane to deliberately infect people with viruses, but this happens by accident all the time. A viral infection may begin with aching, swelling, malaise and mild fever. Although some viruses can be fatal or debilitating, often, we notice little or nothing, or recover fully.

Viruses — and their human hosts — are that variable.

Viruses now under consideration in the struggle against cancer include herpes simplex, the cause of cold sores; measles, cause of epic epidemics through history, and reovirus, a widespread infection that, handily enough, causes no known disease.

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Three-part virus life cycle, virus entering cell, replicating and then bursting the cell.

Oncolytic viruses are designed to emulate the normal infection process, where the virus takes control of the cell to make more of itself, and then ruptures and kills the cell, releasing more virus.

A crisis of lysis?

Still, curing disease with an agent that causes disease reminds us of the bad old days when radium or mercury were considered medicine, and Cripe acknowledges some skepticism among his colleagues. “The whole field is still an area where people who are not involved say it’s interesting, but I will believe it when I see it. When we get the first FDA approval, that will be proof of principle. This is at least going to be another tool in the armamentarium for fighting cancer.”

In the past few years, researchers have shown, in lab dishes and lab animals, that viruses can home in on tumor cells and kill them by exploding – the process of lysis. Tack on “onco-” for cancer, and we meet the “oncolytic viruses.”

No oncolytic virus has yet attained FDA approval, but there are many signs of progress:

A preliminary test of a virus/vaccine combination against advanced melanoma, in 50 patients, had “stunning results,” says Howard Kaufman, associate dean of Rush Medical College in Chicago. Eight patients recovered completely and four partially responded to the treatment. The results were so good that the researchers launched a larger, phase III trial that could provide evidence needed for Food and Drug Administration approval.

A 2012 study1 showed that injecting a reovirus into the blood caused it to “hitchhike” on blood cells and spread through 10 bowel cancer patients. Intravenous delivery, if it works generally, is much simpler than trying to inject every tumor.

A virus called Onyx 015 added no toxicity to standard chemotherapy in 40 head and neck patients2. Sixty-three percent of the patients responded, compared to 35 percent who would be expected to respond to chemo alone.

A preliminary test of reovirus3 against head and neck cancers showed the combined potential of virus plus chemotherapy. The cancers shrank in about one-third of patients who could be evaluated, and disease stabilized in another third, and all signs of cancer disappeared in one patient. “We saw really very impressive response rates,” said Kevin Harrington, oncologist at The Royal Marsden hospital in London, via press release. “These are patients whose cancers had grown despite a great deal of previous treatment. … We’d expect that the average response rate to chemotherapy alone might be as low as single digits figures and the average survival would be somewhere between three to four months.” In the study, average survival was seven months.

How do oncolytic viruses work?

Many types of viruses are under investigation, Cripe says. “There are animal viruses that do not cause disease in people, or human viruses that don’t cause disease, like reovirus.” Viruses can also be genetically hobbled to prevent their running amok.

Using a virus to fight cancer “is not a new idea, it’s been tried for nearly 100 years, since viruses were discovered to kill cells,” says Cripe.

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Black and white photo of discoverer of bacteriophage with his hands crossed on his knee, dressed in a British military uniform and looking directly into the camera.

In 1892, a Russian botanist identified a virus for the first time and 23 years later Frederick Twort (pictured above) was the first person to describe viruses that infect bacteria, or bacteriophages. An Englishman, Twort discovered a bacteriophage, which he called a bacteriolytic agent, in his London laboratory and published the results in The Lancet. Now, almost 100 years later, scientists are using viruses to attack and kill cancer cells.

But if viruses are so great (remember that nobody has proven they are magic bullets against cancer) why the delay? “We went on a long, winding road; it’s only now that the science has matured sufficiently that we can manipulate viruses to our liking, clone in genes, endow them with other properties that make them safe,” says Cripe. “We know enough about cancer biology, cells, viruses, and the immune response, so we are now in a position to harness what I think is a very powerful effect of nature.”

Choosy, choosy!

Traditional cancer treatment is as selective as a shotgun: Radiation and chemotherapy attack fast-dividing cells found in tumors, and in the gut, bone marrow and hair follicles.

The inevitable side effects — hair loss, nausea, weight loss, treatment-induced leukemia — don’t just make patients miserable for the duration. They also limit treatment options.

And so the holy Grail in cancer treatment is selectivity: Identifying and killing tumor cells, without harming normal cells.

Viral selectivity can take many forms. For example, a virus can be engineered so its genes do not work in normal cells, or it can make tiny bits of RNA that regulate which genes work and which lie dormant. Or they can, like reovirus, multiply only in cells with a “ras” mutation.

Interfering with interferon

Ras, named for its discovery in rat sarcoma, is a cellular switch that activates numerous growth signaling pathways that are normally used when a cell grows or divides. These growth pathways are also critical to making more virus and more tumors, says Cripe. “To turn the cell into a virus factory, a virus has to turn on a bunch of genes for making nucleic acids, proteins and enzymes. The virus wants the cell to rev up, so the virus can use the same things a cell needs to grow and divide.”

Among other effects, a ras mutation interferes with the interferon network, which normally protects cells by slowing this production of proteins and DNA. “The interferon pathway was named because it interferes with virus infection,” Cripe says. “Once the interferon protein is expressed, it forces a lot of other genes to turn on and shut down those growth pathways.”

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3 vials of interferon medicine

Interferon was touted as a wonder drug in the 1980s, and although it’s no magic bullet against cancer, several interferons are on the market for treating diseases like cancer and multiple sclerosis.

Reovirus, an oncolytic virus now under intense study, can enter most cells, but it only reproduces if a ras mutation has closed the interferon pathway. As a result, the virus’s “kitchen” is stocked with plenty of those essential proteins and nucleic acids.

And thus the ras defect, found in up to two-thirds of tumor cells, makes those cells vulnerable to reovirus.

Selectivity can work in other ways, says Kaufman, who directs the Rush University Cancer Center. “Oncolytic viruses can infect a wide range of cells, and probably do, but some viruses [including OncoVEX, which he is studying in melanoma] have been rendered a little less powerful. In order for them to really divide and kill the cell, they need a big pool of nucleic acid [used to make DNA or RNA]; they can’t assemble it themselves.”

Although most normal cells lack such a supply of nucleic acids, “cancer cells are abnormal to begin with,” he says, “and there is a large pool of nucleic acid because they have to divide so often. The virus can take advantage of that; if they are only able to grow inside a cancer cell, those are the cells they kill, and that’s why the oncolytic virus is more specific than radiation or chemotherapy.”

Although the OncoVEX-melanoma trial will not use chemotherapy, oncolytic viruses seem ideal for combination therapy, as they have, by all accounts, minimal side effects (typically including fever and aching). Clinical tests already under way are comparing the activity of oncolytic viruses, combination therapy, and chemotherapy alone.

Methods of an experimental anti-cancer virus: Reolysin.

A combination of assaults

But exploding cells is not the only way that oncolytic viruses can attack cancer. Viruses, after all, usually spark an immune response, and that is the second half of their allure, says Kaufman, who is leading a 430-patient phase III study of OncoVEX in melanoma.

OncoVEX is oncolytic, so it can directly kill tumor cells, but, “part of the goal is to take a dying tumor cell and initiate a vaccine response,” says Kaufman, “in a kind of individual self-vaccine.”

Derived from a test vaccine against herpes virus, OncoVEX contains the granulocyte and macrophage colony stimulating factor gene, which “has a particular effect on the dendritic cells that initiate the immune response,” says Kaufman. “Dendritic cells search through the body for potential antigens, bacteria, virus or tumor cells, and activate the T-cells that go back and directly fight the cancer.”

This immune attack seemed to work in a preliminary study, completed in 2010, Kaufman says. “Even tumors that were not injected could be destroyed by the immune system. If we injected a tumor in the skin, sometimes a lung or liver tumor did go away.”

We had to comment that medical magic bullets always seem to misfire, and that oncolytic viruses sound too good to be true. “In a way, they do,” Kaufman admits. “It’s well tolerated, can be done in the office with very few side effects.”

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Woman connected to intravenous tubes administering chemotherapy.

Although she’s smiling, we’re guessing that this patient would rather not have to undergo chemotherapy, with its attendant side effects. If oncolytic viruses continue to prove themselves, they could either replace chemo or become part of the treatment regime.

As leader of the melanoma trial, Kaufman does not know who is getting the virus. But he thinks he’s seeing something good. “I saw a patient this morning, who said, ‘I’m so happy I don’t need surgery, toxic drugs.'”

The real proof will come when a randomized, controlled clinical trial proves that an oncolytic virus — whether OncoVEX or something else — provides a significant survival benefit.

The larger melanoma trial, like several others now under way4, should give a definitive answer, Kaufman says. “I believe we will learn whether it is really effective in a larger number of patients. It’s important to see the long-term outcome. Some of my patients are two-plus years, and have no disease. When we get a complete response that seems to be durable, we are very cautiously optimistic that this is a major advance.”

The question of resistance

Cancer cells are brilliant at evading our weapons; when chemo or radiation works, tumor cells often evolve resistance. The same could happen with oncolytic virus, says Cripe. “If the virus depends on a particular receptor [to enter the cell], it can [find a way to] turn that receptor off. But it only takes one infectious virus particle to kill a cell, and if every cell that is infected gets killed, the tumor cells don’t have the opportunity to mutate and develop resistance. Tumor cells may or may not be receptive to a given virus, but if they are, it’s unlikely they can change, as they will get killed.”

The situation differs from chemotherapy, Cripe says. “If chemotherapy inhibits an enzyme, one cell may figure out how to overcome this. With a virus, it’s all or nothing.” Tumor cells will not see the virus, so they will have no reason to mutate. “If they see the virus, it will kill them,” Cripe says.

But cancer teaches that miracle cures never seem miraculous in the long run. Magic bullets can miss their target. Progress takes time. And, as oncologists remind themselves, “cancer is smarter than we are.”

– David Tenenbaum

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Terry Devitt, editor; Emily Eggleston, project assistant; S.V. Medaris, designer/illustrator; David J. Tenenbaum, feature writer; Amy Toburen, content development executive

Bibliography

  1. Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients, Robert A. Adair et al, Science, 13 June 2012.
  2. Vasey PA, et al. Phase I trial of intraperitoneal injection of the E1B-55-kd…J Clin Oncol 2002; 20: 1562–1569.
  3. Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus …, Eleni Karapanagiotou, et al, Published OnlineFirst February 7, 2012; doi: 10.1158/1078-0432.
  4. Clinical development directions in oncolytic viral therapy, RM Eager and J Nemunaitis, Nature, published online 25 March 2011.
  5. Cancer-killing virus waits in the wings
  6. Interactive atlas of U.S. cancer statistics
  7. Mesmerizing reovirus animation
  8. American Cancer Society’s 2012 Cancer Facts & Figures
  9. Research findings on using viruses to fight gastrointestinal cancer
  10. Cancer survival rate: What it means for your prognosis