Cancer vaccines: New approaches
Research into cancer vaccines has waxed and waned over the years, advancing more slowly than other types of immunotherapy research. Novel approaches are clearly needed. And that's just what Mayo Clinic investigator Richard G. Vile, Ph.D., is bringing to the table, with ideas that are described as incredibly creative, original and even eccentric.
At the Mayo Clinic Cancer Center in Scottsdale, Ariz., researchers are poised to inject a customized virus into the tumors of up to 48 patients with hepatocellular carcinoma, one of the most common and aggressive types of liver cancer.
This virus is actually an experimental vaccine built around the vesicular stomatitis virus (VSV), an ancient cousin of the rabies virus. In collaboration with Glen N. Barber, Ph.D., at the University of Miami, the laboratory of Mayo Clinic immunologist Richard G. Vile, Ph.D., reconstituted the wild-type VSV to a high level of purity that doesn't exist in nature. Through a series of chemical reactions, the researchers coaxed the virus to accept a foreign gene called interferon-beta (IFN-beta) into its own genetic code, and then allowed the virus to multiply in a controlled environment.
The result is a cancer assassin — a precisely engineered vector that can slip into liver tumors undetected and deliver its genetic payload with minimal harm to the patient.
"We see a double-whammy effect of killing via virus and via the immune system," Dr. Vile says of preliminary studies. "The viruses are injected directly into the tumors, and what we see is that with liver cancer, the virus replicates very well and lyses (destroys) the tumors."
In pretrial studies, Dr. Vile showed that the vaccine's IFN-beta protein acts like a red flag to the body's immune system. This provokes a potent response from white blood cells and then bolsters the trail of chemical markers called antigens, which helps the immune system recognize the tumors.
How well the vaccine works in patients should become clearer in the near future. Mitesh J. Borad, M.D., a Mayo Clinic hematologist and oncologist, is leading the clinical trial at the Scottsdale campus of Mayo Clinic, and expects it to be underway in 2012.
"These patients are anxious for new experimental treatments," Dr. Borad says. "This offers the potential for cures — maybe not in everybody, but in at least a small proportion of patients."
Fortunately for these patients, Mayo Clinic has a comprehensive infrastructure to support this type of project, including the manufacture of clinical-grade viruses in the Viral Vector Production Services facility at Mayo Clinic in Rochester, Minn., and the completion of FDA-mandated pharmacology and toxicology testing under the direction of molecular researchers Mark J. Federspiel, Ph.D., and Kah Whye Peng, Ph.D.
Dr. Vile and Mayo Clinic researcher Stephen J. Russell, M.D., Ph.D., who is the Richard O. Jacobson Professor of Molecular Medicine, chose to focus on hepatocellular carcinoma with their vaccine research for a couple of reasons. For one thing, even with aggressive treatment, the outlook for people with this kind of liver cancer is often grim, with survival usually marked by months. Also, the vesicular stomatitis virus shows an unusual preference for infecting and killing liver cancer cells.
"We saw a need at Mayo Clinic, Arizona, so we decided to test recombinant VSV in a liver cancer model," Dr. Russell says. "This will be the first time anywhere for patients to intentionally be injected with any kind of VSV, widely regarded as one of the most promising oncolytic viruses and vaccination platforms around."
Dr. Vile's enthusiasm is infectious. If this expatriate Brit can be persuaded to turn away from his research journals, he'll expound on anything from Washington Redskins football to English national cricket — perhaps even molecular biology. His peers describe his thought process as unconventional. He refuses to follow the herd and has a track record of designing unusual studies that work in ways few ever expected.
"Richie has the ability to inspire all of us," says University of Leeds researcher Alan Melcher, Ph.D., a long-time friend and frequent collaborator with Dr. Vile. "When we hit a point where somebody thinks things aren't going to work out in the way we'd hoped, Richie steps in. ... He pushes us to keep going."
Nearly 30 years ago, as a young researcher at London's Royal Marsden Cancer Center, Dr. Vile watched patients undergo experimental and painful chemotherapy. "The thing that struck me — and still stays with me — is the savageness of those therapies," he says. "I thought 'How hard that must be. They're doing everything they can, and these people are still suffering so terribly. Surely there must be a better way.' "
Finding another way
Dr. Vile's lab continues to search for better ways to kill cancer with fewer side effects — a so-called magic bullet that targets tumors and leaves the rest of the body unscathed. A hallmark of cancer is rapid growth and tumor mutation, which results in treatment resistance as the disease progresses, says Jill O'Donnell-Tormey, Ph.D., executive director of the independent Cancer Research Institute in New York City, which focuses exclusively on cancer immunology.
Researchers target tumor antigens with gene therapies in the hope that the body's immune system will recognize the tumors as foreign, even as the cancer adapts to thwart their efforts and sends out chemical signals, such as transforming growth factor-beta, which eclipse tumors from the immune system's antigen receptors.
Dr. Vile estimates that most cancers have about 100 antigens or more — no one really knows for sure — that the immune system could recognize if only the cancer cells could be programmed to stop secreting these chemical distractions.
But another of Dr. Vile's recent successes with a different kind of cancer could help diminish the likelihood of tumor "escape." His laboratory has identified three keys to the melanoma antigen library: neuroblastoma-RAS (nRAS), cytochrome C1, and Tyrosinase-related protein 1 (TYRP1).
These protein chains dangle from melanoma tumors like microscopic targets in an ocean of complex chemical systems and could become additional targets for custom-built viruses. In other words: Train the immune system to recognize these targets, and the body, when vaccinated, will destroy skin cancer like it does a seasonal flu.
The trick, Dr. Vile says, is to program the immune system to recognize these markers and prevent tumors from immune escape through mutation.
Creating drugs to target such antigens, however, is time consuming, and many large pharmaceutical companies view cancer vaccines with apprehension, Dr. O'Donnell-Tormey says. Couple that with tumor mutation and the diverse immunosuppressant effects of the late-stage cancers, and human studies can prove unappealing to investors, Dr. Vile says.
"It's often the problem that by the time you identify one antigen and administer treatment, the vaccine is no longer effective," Dr. Vile says.
Bullets or buckshot?
With collaborators in the U.K., Mayo Clinic researchers may have discovered a way to sidestep this frustration by loading their vaccine arsenal with a broad gamut of genes that are present in healthy tissue. Prostate genes for prostate cancers. Melanocytes for melanoma. Liver genes for liver cancer. Bronchial or goblet cells for lung cancer. And so on.
"I do believe we can develop therapies that will knock them off, one by one," Dr. Vile says.
A mouse model study published in Nature Medicine showed that delivering an entire library of human DNA through the vesicular stomatitis virus may help shrink or eliminate tumors in advanced stages of melanoma and prostate cancer. This novel approach uses a library of genetic information (complimentary DNA, or cDNA) from healthy human prostate or melanocyte tissue to trigger a more robust response from the body's immune system.
"These antigens are kind of like needles in a haystack — they're really hard to isolate in the lab," Dr. Vile explains. "But the immune system is different. If there are a hundred needles in a haystack, the immune system is so sensitive that it can pick them out."
Rather than develop vaccines to tumor antigens one by one, as most pharmaceutical companies and cancer researchers have done, Dr. Vile threw the kitchen sink at cancer. So far it's working.
Geneticists parsed DNA from healthy human prostate and melanocyte cells into individual strands of RNA. They amplified the individual RNA into a library of millions of identical pieces through a polymerase chain reaction. These amplified genes (cDNA) were then cloned into swarms of VSV and administered to mice with advanced-stage tumors. The tumors shrank in a matter of weeks, with no apparent side effects.
"When we came up with this idea about three years ago, we thought: If tumors can mutate and escape immune response with tumor-specific antigens, why not just try exposing them to the whole thing?" Dr. Vile says.
The study showed promising results in mouse studies, and Mayo Clinic is gearing up to begin more in-depth studies.
"What we're seeing is that by exposing the mice to a collection of antigens, we're getting a better immune response than if we just used one or two," Dr. Vile says. "We believe that, somehow, the immune system is able to ignore those antigens that are part of the healthy tissue and attack only those, or some of those, that are associated with the tumor."
If things go smoothly, Dr. Vile hopes to have clinical trial data within five to 10 years.
Exploiting the range of these tumor-specific antigens is part of what makes Dr. Vile's research unique, says James Gulley, M.D., Ph.D., director of the Clinical Trials Group within the Laboratory of Tumor Immunology and Biology at the National Cancer Institute.
"One advantage it does have ... is the potential to elicit a broader immune response," Dr. Gulley says. "The use of the cDNA library is what makes it unique."
Dr. Russell says he's eager to see Dr. Vile's research translated into clinical trials. "This will be a huge clinical milestone," Dr. Russell says. "It's a wonderfully orchestrated thing in which Richie plays a pivotal role."
It was Mayo Clinic's ability to transform discoveries into treatments that attracted Dr. Vile to the institution in the first place.
"Mayo has a reputation for translating research into the clinic — that's what they do," Dr. Vile says. "What gets me up in the morning is the sense that the work we do here could give patients a chance to live longer and with less pain."
— November 2011