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ONCOLOGY Unleashing One Human Scourge Against AnotherScientists Clear Hurdle in Effort to Destroy Virulent Brain Cancers with Viruses In the August Nature Medicine, Harvard researchers report they are beginning to understand--and dismantle--a barrier that has stymied earlier attempts to create a viral treatment for brain cancer. They hope eventually to infuse a virus targeted against tumor cells into blood vessels feeding the patient's brain in a simple procedure resembling angiography. Usually a powerful immunity thwarts tumor-killing virus particles as soon as they enter the bloodstream, so that they never even get to infect a tumor. The HMS researchers found, however, that a single dose of an approved chemotherapeutic drug can lower that barrier, allowing the virus to reach and rage through human tumors implanted in rat brains and in some animals to expunge the tumors. "This treatment occurred in a severe and highly relevant animal model. It is more efficient than anything we have done before," says Antonio Chiocca, HMS associate professor of surgery at Massachusetts General Hospital's Charlestown campus, who led the study.
 Within two days, a cancer-killing herpesvirus infused into the brain's vasculature has raged throughout two human gliomas implanted into the cerebrum of rats (left). A third tumor in the animals' thalamus also was infected (not shown). After four and eight days (middle and right), the tumors have shrunk. Some treated animals survived long-term, while all control animals died within two weeks. Courtesy of Ennio Chiocca The field of training viruses against brain cancer is at the early clinical stage. One virus is in a phase I trial elsewhere, and Chiocca will soon begin testing another one developed by a California biotech company. Both approaches inject the virus directly into a tumor mass, where it cannot easily escape and spread to tumors elsewhere in the brain. Brain cancer is so deadly--most people diagnosed with malignant glioma die within a year--because it seeds the brain with multiple tumors that neither surgery, radiation, nor chemotherapy can remove. That is why Chiocca hopes his new approach of pervading the brain with blood-infused virus particles will advance the field once initial protocols have proven safe. New Stab at an Old Idea The idea of using oncolytic viruses dates back almost a century when researchers injected weakened rabies virus into cervical cancer. It was sidelined by the advent of chemotherapy agents in the 1960s, but re-emerged in the '90s after decades of research had failed to improve significantly the outcome for brain cancer. Recent research began as a form of gene therapy, where scientists used replication-deficient viruses to ferry therapeutic genes into the tumor. One such approach, developed by Xandra Breakefield, HMS professor of neurology at MGH, inserted into the virus a gene that increased the cancer's sensitivity to the chemotherapy drug gancyclovir. Though safe, this attempt was not clinically effective in its initial form, in part because the virus lingered around the injection site. After these setbacks, Chiocca and others returned to viruses that do replicate, though in a genetically restrained way. Using herpes simplex virus, his research moves along several parallel tracks that he hopes will eventually merge into an effective therapy. While an early strain is currently undergoing safety tests in primates in preparation for a clinical trial, the researchers are already trying to develop later-generation improvements in the lab. One involves the current paper dealing with the host's resistance to viral therapy. Previously, Chiocca was confounded by the fact that his herpes simplex strain wiped out cultured cancer cells within a day, yet did nothing when he infused experimental animals with as many as a billion particles. Something in the blood's plasma was clearing the virus--a mysterious mechanism that might foil all viral therapies, he says. In this paper, Chiocca and his collaborators begin to identify this activity as part complement, a well-known enzyme cascade, and part IgM antibodies that course through the body even in the absence of any particular pathogen. The two interact, and other factors are probably at play as well, says Chiocca. The researchers found that with this obstacle removed, delivering herpesvirus therapy through the bloodstream suddenly works. Cyclophosphamide--a drug used in cancer, autoimmune diseases, and transplantation--can prevent the production of antibodies. Chiocca's group found that one dose lowered IgM levels enough for the virus to avoid elimination.
 Though Chiocca cannot predict whether these results will hold up in the clinic, he says the virus's performance in this model of brain cancer makes him hopeful. "This is the first time, to my knowledge, that someone has effectively infected three large tumors in a rat brain through the vasculature and caused all three to shrink," he says. A small percentage of animals even survived long term with the tumors gone--and this in a model in which all untreated rats die within two weeks of having the tumors implanted. His work suggests that current clinical trials of oncolytic herpes strains could boost their efficacy by administering cyclophosphamide as well. Wanted: A Picky Eater Along a second track, Chiocca and his colleagues are trying to develop new viral strains that distinguish more clearly between normal and cancerous cells. Scientists are watching the first human tests of herpes simplex in brain cancer with trepidation, because this virus, when unchecked, can cause encephalitis and meningitis. Yet scientists were long caught in a quandary, because as they improved the virus's safety, they were trading in its efficacy. Chiocca's current virus strains grow preferentially in tumor cells. That is because mutations in the p16 tumor suppressor pathway--seen in many brain cancers--result in an overproduction of the enzyme ribonucleotide reductase. This "rescues" a mutation in the viral gene for that essential enzyme. In other words, the virus exploits for its growth the genetic changes that made the cell cancerous in the first place. But this control mechanism is not airtight. To make the virus safer, Chiocca and others had also disrupted a virulence gene that blocks the infected cell's defensive suicide reaction, forcing it to stay alive and host the virus's growth. But the lack of this gene, called gamma-34.5, again hobbled its ability to spread through the tumor. In a report due out next month, Chiocca and colleagues describe how they have reawakened this virulence gene specifically in tumor cells. They did so by placing it under the control of a promoter of gene expression that is especially active in tumor cells. "In the tumor, this virus spreads like wildfire, while in normal cells it is a dud," says Chiocca. Engineering a "Supervirus"? A third line of investigation attempts to arm the oncolytic virus with therapeutic genes that make its host cell susceptible to chemotherapy drugs. A paper to appear later this month in Cancer Research describes the combination of two such approaches, one sensitizing cancer cells to the drug gancyclovir and one to cyclophosphamide. This newest virus strain may pack a bigger punch, hopes Chiocca, who is collaborating with Breakefield on this project. Indeed, it was the only treatment able to shrink tumors implanted into mice while its components--the oncolytic virus alone, or in combination with a single chemotherapy-sensitizing gene--merely slowed down tumor growth. Clearly, much genetic tinkering remains before scientists come up with the right virus strain. Meanwhile, researchers need to show safety in the clinic to keep the door open for a possible future treatment. --Gabrielle Strobel |
