By David N. Leff

Name this affliction: "A short-lived tense vesicle followed by a small, painful ulcer at the vermilion border."

It's the common cold sore, or fever blister. Both of these colloquial terms are wrong. You don't have to catch cold, be cold or run a temperature in order to contract herpes simplex type 1 labialis. This common viral infection of the lip lasts a week to 10 days and then it's gone - until the next cold sore pops up.

Now, molecular neurosurgeon Robert Martuza, chairman of neurosurgery at Georgetown University in Washington, has hired that virus for a new job - curing prostate cancer. The title of his paper in the September 1999 issue of the journal Human Gene Therapy tells how: "Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207."

Prostate cancer (PC) is the commonest non-skin malignancy among males in the U.S., and the second most common cause of cancer death. When laboratory tests confirm that the growing prostate gland is indeed cancerous, Martuza told BioWorld Today, "the patient has one of three treatment alternatives - surgery, radiation or watchful waiting, and most people with an initial diagnosis will choose one of these standard therapies."

But often, radiation can't stop the cancer from recurring, driven as it is by the male hormone testosterone, which the testicles pour abundantly into the prostate gland. Some of its tumor cells may no longer need the hormone in order to proliferate, and so metastasize fatally to distant organs in the body. Then, castration - surgical or chemical ablation of the testes - is the last resort.

Martuza and his co-authors have educated their special strain of herpes simplex virus type 1 to kill those tumor cells at each stage of their progression from diagnosis to metastasis. "The major finding in our journal article," he observed, "is that G207, this herpes virus vector that we created, very effectively killed human prostate cancer cells. Our experiments showed that it can be used by both direct injection into the tumor or the prostate gland, or it can be given intravenously for systemic administration against metastatic prostate cancer."

The Georgetown surgeon developed his G207 vector after a decade's research. "Back in the late '80s and early '90s," he recalled, "I came up with the idea of making a virus that could actually replicate within a cancer cell. Since then, other people have taken up the concept with replicating adenoviruses and reoviruses and other vectors as well." (See BioWorld Today, July 28, 1999, p. 1.)

Martuza makes the point that his viral vector's payload "is the oncolytic virus itself. It's quite a different concept from other gene therapy approaches. It works on the principle that herpesviruses know how to kill cells. So what we really did in constructing G207 was to take out genes that allow it to kill normal cells, and letting them kill only cancer cells."

Oncolytic Vector Kills Black-Hat Tumors, Spares White

"G207," he went on, "enters the cancerous cell and takes over its metabolism, makes multiple copies of itself, then kills the cell. Those viral copies can get out and infect other nearby cancer cells. But we've designed G207 in such a way that when it enters noncancerous cells - for example the neural tissue that surrounds the prostate - it will not kill them."

Martuza explained this neural component of the prostate gland: "The major complications of treating men with prostate cancer," he pointed out, "whether by surgery or radiation, is really damage to the neurovascular bundles around the prostate, leading to either incontinence or impotence. So the idea here would be that we have a vector capable of killing the cancer cells without harming the adjacent normal nerves.

"This selectivity is based on two things," he continued. "We inactivated two different genes in the wild-type virus. One gene, U_L39, encodes the enzyme ribonucleotide reductase [RR], which is necessary for the virus to replicate. Cancer cells have fairly high levels of RR, and although the virus doesn't have this gene, it can borrow it from the cancer cell. However, normal, noncancerous cells have very low RR levels, so the virus really can't grow effectively in normal cells, but can still grow and kill cancer cells.

"In addition, we inactivated another gene, g₁34.5, which allows the virus to grow, particularly in brain or nervous system tissue, or any post-mitotic cell. When we take that gene out, the virus can still grow in cancer cells."

The co-authors chose two highly malignant prostate cancer cell lines to pit against their G207 vector in experimental nude mice. "We implanted those PC cells under the skin of those mice," Martuza recounted, "and allowed the tumors to grow. Then we inoculated them directly with G207 virus. Those tumors regressed, and were completely eradicated in about 25 percent of the animals. But in control mice, inoculated with no virus, the tumors continued to grow until the animal had to be either sacrificed or died."

Shot In Tail Vein Shoots Down Metastases

In another experiment, the co-authors showed G207 could cure previously irradiated, recurring tumors, after which, "The next thing that we did," Martuza related, "was to see if we could treat a metastatic tumor. So we took the same two PC cells - one hormone sensitive, the other insensitive - and implanted them under the animals' skin, in the flank, up near their shoulder. Then we injected the virus not into the tumor directly but into a tail vein, which let it go throughout the whole body, and then measured the tumor size. Again we got complete cures in approximately a quarter of the animals."

NeuroVir Therapeutics Inc., a biotech company moving from Vancouver to San Diego, has licensed G207 from Georgetown University. Martuza is a consultant to the company. "We formed an association with NeuroVir," he told BioWorld Today, "which produces the clinical-grade virus we use in our experiments."

Martuza said, "This was really the first in vivo study, and to get these results we simply gave the mice two injections. Now we're looking at multiple-injection strategies and at other possibly more effective vectors of a similar type to the present G207. But this is really to my knowledge the first time that an intravenous systemic treatment has been used with herpesviruses to cure a metastatic tumor."

He and his co-authors are actively envisioning clinical trials in prostate cancer patients. "We have done preclinical safety studies, which look very good," he said, "and I don't really see any barriers to it.

"But what we want to do before we inject people is make sure that it's safe - and it looks very safe. Our final preclinical safety study," Martuza concluded, "will be direct injection into the prostate glands of primates."