By David N. Leff
Many a movie and sitcom bases its plot line on the age-old notion of setting a thief to catch a thief. And often the cop who does the setting turns out to be a criminal himself.
This time-worn drama takes on a new shine when transferred from the screen to the laboratory, where viruses - usually the enemy pathogen - are set against malignant tumors. And here the law enforcer is revealed as a renegade member of the patient's own immune defense squad.
Stay tuned for the scenario that unfolds in the just-published August issue of Nature Medicine. Its title tells it all: "Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses." The senior author of this script is brain surgeon E. Antonio Chiocca, an associate professor of neurosurgery at Harvard Medical School, and its affiliated Massachusetts General Hospital.
"The occurrence of multiple tumors in an organ," states the article's opening line, "heralds a rapidly fatal course. The treatment of tumors that have seeded multiple sites in an organ such as brain or liver, remains palliative."
"Among the most incurable forms of malignancy," Chiocca told BioWorld Today, "are liver cancers that have multiple metastases, such as colon carcinoma metastatic to liver. Those are very untreatable. And there's a primary brain cancer called glioblastoma," he went on, "which can present with multiple tumor foci within the brain. It's probably the most incurable form of brain cancer."
In experimental attempts to cure glioblastoma some- day, Chiocca and his co-authors have enlisted herpes simplex virus (HSV), better known as the pathogen that causes genital lesions and cold sores. "First of all," he explained, "there are different types of herpesviruses that can be genetically altered, and all of which have displayed antitumor activity. The HSV we've used has a particular deletion in a gene called ICP6, which encodes the ICP6 protein.
But there are other oncolytic viruses," he added, "some of which are cited in our paper. For instance, there is an adenovirus called Onyx 015 that's made by a biotech company out in California. It will replicate and kill tumor cells in a relatively selective fashion. Then there is a reovirus mutant, reported in Science last year, which also has been implicated as a potentially relatively selective oncolytic virus for tumors with an activated Ras [oncogene] pathway."
Viruses Briefed To Kill Tumors, Not Patients
To describe how these cancer-killers work, Chiocca took as an example "the herpesvirus that we've used. About 10 years ago this particular mutant was shown to replicate selectively in dividing cells, compared to quiescent cells. The reason for that is that when its gene has been deleted the virus cannot replicate in non-dividing cells. It will either abort infection of the healthy cell, or enter a latent state. However in rapidly dividing tumor cells, viral replication is complemented by factors within the tumor that allow it to grow.
"Each one of these viruses," Chiocca pointed out, "has different mutations, and each one its selective target. Different pathways within tumors make them more tumorigenic. And therefore the concept is that you can start removing genes from different viruses, and the fact that they make tumors grow can also make these viral mutants grow."
What makes these reformed viruses stop growing, and stop slaying tumors, as Chiocca reported, is a friendly-fire counterattack by elements of the body's immune system. In in vivo experiments using rats with three glioblastomas implanted at separate sites in their brains, he and his team found that, "for the first time, at least in our lab, and I think in other labs, we've been able to show that after treatment with the oncolytic virus - without the intervention of some undefined immune system - we can cause all three tumors in these animals' brains to involute, to shrink. And that suggests a possible treatment modality for patients who have these types of cancers.
"I think the basic scientific finding of this article," Chiocca observed, "is that the innate immune response of the animal - and probably of humans - imposes a barrier, and impedes the successful infection and propagation of such oncolytic viruses in tumors. What we found were some of the components of the innate immune system, such as complement and preimmune immunoglobulins, which appear to impede the ability of the virus to infect and kill tumors."
He continued: "To remove these components in a transient manner, we used a drug called cyclophosphamide, which is an immune suppressor. This treatment allowed more viruses to survive in the circulation and in the infected tumors. They were therefore more efficacious at killing these tumors." He added that on this score, "A small percentage of the animals even survived long term with the tumors gone - and this in a model in which all untreated rats die within two weeks of tumor implantation."
Primates Within A Year; Human Phase I In View
"What we plan to do next," Chiocca said, "is to proceed within 12 months to preclinical toxicity studies, using primates. If these show that this treatment is relatively safe, we can design an appropriate clinical Phase I trial of this type of therapy for patients with multiple tumors in an organ." He expressed the hope that "this will lead to a brain-cancer treatment that involves injecting a tumor-specific virus into the patient's bloodstream, much as in angiography.
"I think that these oncolytic viruses are very versatile systems," Chiocca opined. "They possess multiple genes that can be deleted. We're hoping that we can engineer the super-virus, which will be even more selective in targeting and killing tumor cells while sparing normal cells. Moreover," he suggested, "you can also engineer these viruses to be gene-therapy vectors, where you place various anticancer functions into viruses, which they would deliver to the tumor.
"We have made viruses," Chiocca concluded, "that are not only oncolytic, but also deliver genes that increase the sensitivity of the tumor to chemotherapeutic agents, or to radiation, thus helping increase - rather than impede - immune responses against the tumor."