By David N. Leff

Steve McQueen, the legendary movie actor, died of it. So did Admiral Elmo Zumwalt, of nuclear submarine fame. And a sitting U.S. Congressman has the disease.

It's malignant mesothelioma, a cancer that transforms the membranous mesothelial cells that enclose lungs, heart, the inner abdominal cavity and the outer walls of the intestines. It's a mercifully rare disease, but otherwise merciless.

"About 2,500 deaths due to mesothelioma occur annually in the U.S., but the number is growing," observed pathologist and molecular virologist Michele Carbone, at Loyola University in Chicago. "Approximately 80 percent of patients with this form of cancer have had some occupational exposure to asbestos." That contact ranged from the fiber's uses in household and industrial insulation to brake linings and gaskets, to paint fillers and chemical filters - to actually mining asbestos in deposits throughout the world.

But the cancer was in no hurry. It took anywhere from 25 to 40 years for inhalation of the microscopic fibers to eventuate in full-blown malignancy. Meanwhile, of course, Western industrialized nations have vigorously cleaned up their act of asbestos contamination. Which means that mesothelioma has become a malady of the aged - people in their 60s and 70s.

"Patients will usually present," observed thoracic oncologist Harvey Pass, at Wayne State University in Detroit, "with symptoms of shortness of breath. They are found to have fluid in the chest. At first, CAT scans don't show any solid disease. Then six months down the line they get some pain, with progression - meaning a solid tumor - and only then a definitive diagnosis of mesothelioma.

"The median survival of all patients who present with mesothelioma," Pass went on, "is eight to 18 months. And half of those patients, from the time of diagnosis, will be dead within that 10-month time frame. But if they get no treatment - surgery, radiation, chemotherapy - just supportive care, then 50 percent are dead within seven months."

However, an unexpected blip on this asbestos screen popped up during the late 1950s and early 1960s. That was when the U.S. population was inoculated with polio vaccine made from cultured monkey cells. This was found to be contaminated with simian virus 40 (SV40). It was no longer used after 1963 - but it set Carbone thinking.

SV40 Scores 100 Percent In Hamsters

In 1993, he injected SV40 into the chests of hamsters, and 100 percent of them contracted mesothelioma - with no asbestos in sight.

The current Proceedings of the National Academy of Sciences (PNAS), released electronically on Aug. 22, 2000, carries as its lead article a paper titled: "Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity." Its co-senior authors are Michele Carbone and Harvey Pass.

"We knew that SV40 is by far stronger than anything else to induce mesothelioma in animals," Carbone told BioWorld Today. Then we knew SV40 was present in human tumors. But we didn't understand two things: What was the role, if any, of SV40 in this human tumor? Of all the cells in the human body, why mesothelia?"

He continued: "When SV40 infects a human cell, it kills the cell eventually. Obviously, a killed cell cannot become malignant - and the phenomenon of malignant transformation is extremely rare. It can occur only if by chance virus becomes integrated into the host cell's DNA. Also, if SV40 was doing something, was it interacting with asbestos or totally ignoring it?

"As reported in PNAS," he recounted, "we found that mesothelial cells are very different from other cells. If you infect other cell types with SV40, only a minority of them become infected. In this minority, the virus replicates and kills the cell, which, of course, can't become cancerous. Only very, very rarely will the infection give rise to a transformed cell.

"So when we infected close to 100 percent of mesothelial cells with the virus, we expected all of them would have died soon. Instead, this didn't happen. Only a small percentage of the cells died. Instead, the other cells appeared able to continue to grow, healthy, but expressed the viral transforming protein.

"When we expressed that viral protein, called T antigen, for a prolonged period of time, obviously we were increasing the chance that it could induce the transformation of those cells, because it has more time. So now, combining these two - the larger number of cells in which the virus is working, and the fact that these cells are not killed, they have a multiplicative effect - increasing the chance of malignant transformation.

"In plain numbers," Carbone summed up, "we found that SV40 induced transformation of human mesothelial cells at least 1,000 times higher than other human cell types."

Successful RAID On NIH

As for translating these basic findings into clinical practice, Pass told BioWorld Today, "We've kind of been stymied with regard to standard therapies for mesothelioma, including surgery, radiation and chemotherapy. However," he continued, "I think our team is going to make an impact on the disease with a newer, more novel, immunotherapy.

"Two days ago," Pass recounted, "I received from the National Cancer Institute what's called a RAID - rapid assessment for intervention development - with a favorable score. So a consortium of us, including Dr. Carbone, as well as other collaborators, are going to be able to have the NCI contract out for us to develop GMP-quality vaccinia T antigen, and see if we can actually immunize mesothelioma patients to help those who are T-antigen positive.

"Whether it will work or not we don't know," Pass allowed. "At the same time, there is logic for this vaccine, and apparently the NCI agrees with it."

That logic starts with a Phase I protocol, Pass said. "We'll get a vaccinia viral vector incorporating an SV40 T-antigen construct, and vaccinate mesothelioma patients to see if they mount an immunological response with cytotoxic lymphocytes against target cell lines that are expressing T antigen. In other words," he added, "what we'll be trying to do is very similar to heightening the immune system to make the T cells recognize areas that recognize T antigens - which of course would be those that contain tumor.

"I just got word," he concluded, "that the NCI wants me to come there so we can discuss the contracting and development of the material to get that trial done. I would say it can't begin before a year and a half."

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