Use of Altered Virus to Fight Cancer Looks Promising

December 22, 1998

Use of Altered Virus to Fight Cancer Looks Promising

By NICHOLAS WADE

novel form of cancer treatment has neared the end of its preliminary trials with promising results at the same time as new research has cast doubt on its original rationale.
The doubts, not yet resolved, may mean that the treatment is less harmless to normal cells than thought. But it is also possible that the treatment may be applicable to a much wider range of cancers than previously believed.
The agent of treatment is a genetically altered adenovirus, one of the viruses that cause the common cold. Called Onyx-015 by its developer, Onyx Pharmaceuticals of Richmond, Calif., the virus is injected directly into tumors. Enormous doses can be used without apparent harm to the patient because the virus is designed to kill certain types of tumor cells but not healthy cells.
The treatment is based on recent insights into the basic genetics of tumor cells, and in particular the protective genes that are subverted when a cell becomes cancerous. The virus is designed for specific attacks on the many types of tumor cells that have knocked out a critical gene called p53.
Onyx-015 is being tested in patients with several types of cancer but the trials with head and neck cancers are furthest along. Onyx Pharmaceuticals reported last month that in 16 out of 26 patients with head and neck cancer, or 62 percent, the tumors had shrunk by more than half, and that in six of those patients the tumors had entirely disappeared.
In all cases, the patients received a standard chemotherapeutic drug as well as the virus, because earlier tests had shown the two agents in combination were more effective than either alone.
The results are impressive because the patients were at an advanced stage, all of them having failed to benefit from conventional treatments. But because the test is a Phase 2 trial, designed to explore the most effective dose with only a small number of patients, the results cannot be regarded as conclusive. The company now hopes, with Food and Drug Administration approval, to move to a Phase 3 trial, with enough patients to arrive at a statistically significant outcome.
Dr. James Arseneau, a doctor at the Albany Medical Center, is one of those testing the virus. Of the eight patients with head and neck cancer whom he has treated so far, "three have had really superb results," he said.
"With one guy, the tumor all went away," he said. "In another, there's just an area of thickness but the initial mass has gone. The others had more minor responses. But given the situation, these people are in, with far advanced disease, I think it is really remarkable they have done as well as they have."
Meanwhile, on another track, several researchers experimenting with the Onyx-015 virus in the laboratory say they find it behaves rather differently than Onyx had proposed on the basis of its own laboratory tests. The question of exactly how the virus works bears both on its safety and on the range of tumor types it may be able to kill.
Normal cells have an intricate circuitry of interacting genes and proteins that control their proliferation. The circuitry is designed to make sure that the cells divide when the body requires them to, but to halt or even kill the cell if it attempts an unauthorized division that might lead to cancer, such as after invasion by a virus or damage to the chromosomes. Division is tightly controlled by a system centered on a protein known as Rb. The cell-arrest and cell-suicide programs are under the direction of another protein, p53.
For a cell to become tumorous, it must subvert the division-control circuitry. Many tumor cells have sabotaged the Rb gene and in about 60 percent the p53 gene is also mutated.
Biologists have recently come to recognize that viruses, like incipient tumor cells, must defeat the division-control circuitry and that in the course of evolution, several viruses have targeted the products of the very same genes that are mutated in tumor cells. Adenovirus has at least three genes for this purpose. Its E1A gene makes a substance that disrupts the Rb protein, while E1B-55K blocks the division-arrest function of p53, and E1B-19K jams p53's cell-suicide program.
In 1992, Onyx's chief scientific officer at the time, Frank McCormick, realized that the frequent mutation of the p53 gene in tumor cells created a critical difference between them and the healthy cells that could be exploited by a defective form of adenovirus. An adenovirus lacking the E1B-55K gene that thwarts the division-arrest mechanism of p53 would be unable to replicate in normal cells, because their p53 system would block the division process. But the defective virus could replicate in tumor cells that had disabled their own p53, and go on to attack other tumor cells.
"The concept is a very powerful one," said Dr. Scott Lowe, a molecular biologist at the Cold Spring Harbor Laboratory in Long Island. "Once he told us, everyone said 'Why didn't I think of that before?' "
Onyx-015 is an adenovirus that lacks the E1B-55K anti-division-arrest gene. In preclinical studies, the company reported that the defective virus killed laboratory cultures of p53-deficient tumor cells but was harmless to normal cells.
But in the last few months other researchers have come up with contradictory results that "question the reliability of Onyx's original preclinical studies," said Dr. Steven P. Linke, a molecular biologist at the National Cancer Institute.
"McCormick has an excellent idea and I hope it will work," Dr. Linke said. "But in the new studies, the Onyx virus in some cases is unable to kill tumor cells that lack p53 function. The conclusion would have to be that the killing mechanism is independent of p53, although if the clinical trials are successful, it may not matter too much how the virus works."
Dr. McCormick, who is now director of the cancer center at the University of California at San Francisco, agrees it is now clear that Onyx-015 can replicate in cancer cells with an intact p53 gene, "which is not consistent with the original hypothesis at all." But he believes a new discovery about the genetics of tumor cells goes far toward explaining the apparently contradictory results.
Even in tumor cells where the p53 gene itself is intact, other things may go wrong in the pathways through which p53 operates or is activated. Biologists have recently discovered the genetic relay through which Rb signals to p53 that an improper division is in progress. This gene, known as p14-arf, turns out to be mutated in many tumor cells.

Dr. McCormick says that all tumor cells may have mutations in either the p53 gene or the p14-arf gene, so that either directly or indirectly their p53 system is inactivated. This would explain why Onyx-015 can replicate in tumor cells with normal p53 genes, he said.
As for the reports that Onyx-015 can infect normal cells in laboratory culture, Dr. McCormick said it appears that the process of culturing cells to make them grow outside the body can inactivate p14-arf, again creating the conditions for Onyx-015 to flourish. He noted there was no sign that Onyx-015 attacked normal cells in the living body.
"Viruses are highly conserved and everything they do is for a clear purpose," Dr. McCormick said. "If you accept that the virus makes E1B-55K to neutralize p53, then our original hypothesis has to be true."
Other experts said the suggestion that all tumor cells have knocked out either p53 or p14-arf is plausible but has yet to be fully demonstrated. They said that regardless of exactly how Onyx-015 works, the general idea of using viruses to target the Achilles' heels of tumor cells is highly promising.
"Despite these bumps in the road, I still think it is a very exciting strategy," Dr. Lowe said. "If this virus doesn't work, probably some other virus will."

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