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Scientists at the Duke Comprehensive Cancer Center are harnessing the natural infectious power of four viruses – vaccinia, fowlpox, adenovirus and alphavirus – to provoke the immune system into battling colon cancer cells that hide below its radar screen.

Viruses have been used to attack cancer before, but never with such force of numbers and intellectual resources as the Duke researchers are mounting against advanced colon cancer.

A $10 million grant from the National Cancer Institute is funding the five-year research and clinical project, and Duke is drawing upon the unique intellectual resources of two biotechnology companies in its effort to develop and test some of the most innovative viral vaccine strategies to date, said H. Kim Lyerly, M.D., director of the Duke Comprehensive Cancer Center.

"Cancer has a knack for eluding the immune system and masking itself as friend instead of foe," said Lyerly, principal investigator of the study. "We've designed vaccines that more forcefully present cancer as the enemy to the patient's immune system than earlier vaccines have been able to do."

The key to a successful cancer vaccine is using the virus as a "red flag" to arouse the immune system while presenting a unique element or "fingerprint" from cancer cells as the enemy target for destruction, said Lyerly. Each virus is genetically programmed to target only those cells that carry this unique fingerprint, known as an "antigen." The goal is to use the virus to trick the immune system into reacting against the accompanying colon cancer antigens, said Lyerly. All too often, the immune system sees these rogue cancer proteins as harmless.

In a unique affront against this deadly disease, the Duke team is collaborating with Alphavax Human Vaccines, Inc., and Therion Biologics in its quest to invent anti-cancer vaccines strong enough to trigger the immune system, yet gentle enough to preserve the very immune cells needed to wage war against cancer.

Combining the vast resources of academia and industry to subdue cancer will quicken the pace of testing and evaluation – a process that has taken years or decades in the past, said Lyerly.

Their most promising strategy, he said, is a one-two punch called "prime and boost." Early evidence shows this strategy holds particular promise because of its ability to alert or "prime" the immune system with one vaccine and boost its momentum with a second vaccine. Each vaccine uses a different virus to present the CEA and/or MUC-1 cancer antigens to the immune system as the enemy.

In the past, cancer vaccines have fallen short of expectations because they failed to generate a powerful enough immune response to seek out and destroy the cancer. Even a 60 percent immune response will fail to suppress cancer if the threshold for cancer suppression is 65 percent, said Lyerly. It is hoped this potent one-two punch will elicit a more powerful immune response than has been achieved with previous vaccines, he said.

"We're developing an incredibly diverse arsenal of vaccines in collaboration with the private sector and bringing it all to bear on finding a cure for colon cancer," he said. "Just as we're using the viruses in synergy, we can work in synergy with industry to speed the discovery process for patients in desperate need of novel therapies."

The four viral vaccines are being tested in combination with standard therapies to subdue advanced colon cancer. Testing has already begun with the combination of vaccinia virus followed by fowlpox virus, termed "Panvac-V and Panvac-F." Duke oncologist Michael Morse, M.D., will test whether the vaccine combination can prevent cancer from recurring in patients whose colon cancer has spread to the liver and has been surgically removed.

Morse's approach will bait the immune system with the Panvac-V and trick it into thinking its hitchhiker antigens CEA and MUC-1 are also foreign invaders. To ensure the immune system immediately recognizes CEA and MUC-1 as enemy, the scientists alert the watchful eyes of the immune system -- specialized cells called dendritic cells. Dendritic cells announce foreign invaders to the immune system's fighter "T-cells" for destruction.

The scientists prime dendritic cells in advance by extracting them from each patient's blood and mixing them together with the virus and antigen(s). The combination vaccine is then injected into the patient.

Loading the dendritic cells with virus and antigen in the laboratory ensures that the cells will immediately recognize and "announce" the foreign invaders once they are placed back into the patient, said Tim Clay, Ph.D., associate research professor of experimental surgery.

"By mixing dendritic cells with the viral vector, we ensure that the immune system is notified at once of its presence and that we achieve maximum exposure to the antigen," said Clay.

Success has been elusive in the past because viral vaccines must employ just the right strength of virus to notify dendritic cells but not annihilate them, said Clay. Too strong of a viral vector can kill the very immune cells needed to wage battle. Too weak of a virus will fail to elicit a hearty immune response, he said.

"Each virus tickles the dendritic cells in a different way, said Andrea Amalfitano, Ph.D., associate professor of medical genetics at Duke. "Distinct viruses activate different pathways in the immune system, and in doing so, we hope that one vaccine or a combination will stand out among the rest."

Complicating the scenario is that many patients have built up immunity against common viruses, so their antibodies neutralize them upon contact, said Amalfitano. Using different viruses to deliver the same cancer antigens may overcome this immunity by introducing a new red flag with successive vaccinations, he said.

Designing the vaccines themselves is no small feat and requires a highly developed infrastructure such as that afforded by the Duke-biotech collaboration, said Lyerly. Several of the viral vectors are being developed at Duke, while Alphavax and Therion are providing others.

A team of immunologists, geneticists, oncologists, cell biologists, and biostatisticians from Duke and industry has collaborated for two years to develop each vaccine and design three clinical trials. Scientists evaluate each vaccine's potential in an animal model of colon cancer before they test it in humans.

Once patients are vaccinated, physicians measure each patient's antibody and T-cell response to assess their immune response. Tumor shrinkage and other clinical signs of progress are also measured to assess each vaccine's effectiveness.

To ensure the safety of vaccines, the adenovirus, alphavirus and fowlpox virus vectors are rendered genetically unable to propagate once inside the body. The viruses are partially disabled in the laboratory so they only enter cells once and present the cancer antigen to the immune system. Once their job is done, they can no longer replicate or cause disease, a critical safety feature.

"Single cycle vector" is the phrase for these unique safety systems, said Jonathan Smith, Ph.D., chief scientific officer at Alphavax. "There isn't a continual propagation of virus, which would be dangerous for immuno-compromised patients."
Alphavax Human Vaccines, Inc., is located in Research Triangle Park, NC, and Therion Biologics is located in Cambridge, Mass.