Training the Immune System to Fight Cancer
Mayo researchers are exploring the hypothesis that the immune system plays a significant role in whether or not cancer cells proliferate. Their goal is to develop a cancer vaccine to boost the immune system. The science crosses many disciplines and may develop new therapies for people with breast cancer, ovarian cancer and rheumatoid arthritis.
Immunologist Keith Knutson, Ph.D., works across divisions in research to find answers.
The path from petri dish to prescription bottle is more like a bumpy dirt road than a superhighway. Because unearthing discoveries can require that researchers dig deep into one area of expertise, few ever see the entire stretch of road in their lifetime, leaving treacherous gaps between "basic science-land" and the mecca of the clinic. Enter Mayo Clinic immunologist Keith L. Knutson, Ph.D., a rare breed of scientist who has made a career of bridging those gaps.
"Most of us are trained in one little corner of science, and it can be hard to look beyond that and reach out to researchers who are working in other domains," says Dr. Knutson's longtime collaborator Sherine E. Gabriel, M.D. "Keith has an appreciation and a respect for the entire breadth of research across the translational spectrum, and he looks for connections between his own work in the laboratory — which is world class — and patients in the clinic and people in the community. It seems to come naturally to him, though it is a challenge for many."
A running start
Dr. Knutson developed a culture method for generating pure populations of breast cancer stem cells using tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta).
When combined, they cause transformation of breast cancer cells (MMC) into breast cancer stem cells (ETTM), which are stable in culture and can be studied. MMCTT cells are intermediaries between MMC and ETTM cells. His lab is developing vaccine strategies to target breast cancer stem cells.
One of the latest targets of this collaborative culture is cancer vaccines, which can train the body's own immune system to fight the disease. Many scientists believe that cancer cells arise and are destroyed by the immune system at an alarming rate, with cancer prevailing only when the immune system fails to do its job. This theory of basic biology is being applied to create a new generation of therapies that could revolutionize cancer care.
"We could use the same tactic that eradicated smallpox and other infectious diseases and apply it to cancer," says Dr. Knutson. "We may not totally eradicate cancer, but we hope that by boosting the immune system we could at least give the body a running start in preventing a tumor from growing unchecked." This disease approach is not new for him. Previously, at the University of Washington, his work led to vaccines that are currently being tested in clinical trials to prevent breast cancer relapse. At Mayo, his translational research has already led to two Mayo-industry collaborations aimed at moving two vaccines into people with breast cancer.
The immune system may already play an integral part of current cancer-fighting therapies. For example, the drug Herceptin targets a protein called HER2, which is more abundant on the surface of some breast cancer cells than on normal cells. What isn't clear is if, in addition to directly attacking the cancer cells, the drug also boosts the immune system to send more "soldiers" into the fight.
To answer this question, Dr. Knutson has teamed up with Mayo translational oncologist Edith A. Perez, M.D. — one of the first clinicians to help prove the efficacy of Herceptin — and a longtime collaborator, Columbia University immunologist Raphael Clynes, M.D., Ph.D., whose expertise lies in the mechanisms of cancer vaccines. Armed with a $3 million National Institutes of Health (NIH) grant, the team is looking at the impact of Herceptin on the immune system by analyzing blood and tumor specimens from thousands of people treated with the drug. Both Drs. Knutson and Clynes have developed novel immune assays that are both sensitive and robust enough to measure breast cancer immunity in such large patient populations. Those accomplishments helped attract the NIH funding.
If the researchers find Herceptin works by bumping up the production of antibodies and that those changes are correlated with clinical outcomes, then the drug could be tweaked in the laboratory to make the treatment even more effective against cancer. That tactic is necessary because even though Herceptin is considered a great step forward for breast cancer care, a considerable number of people still do not respond to the drug. By understanding the potential role of the immune system on the potency of Herceptin, the researchers are carving out ways to identify the people who will benefit most from treatment. Dr. Perez believes it is important for patients to know about her efforts to improve and personalize treatment — to give them hope while helping them understand their role in the greater research enterprise.
"Patients need to realize that in order for us to increase the understanding of the biology and improve the cure rates for breast cancer, we need them to be our partners in this team science," Dr. Perez explains. "We need patients' help by letting us collect and test tumor specimens, or even just a few milliliters of blood, so we can do this translational work. I want patients to buy into the relevance of this work as much as I do, so we can better work together to help solve this problem of breast cancer."
Charting the course
Derived stem cells can form tumor-like nodules in culture. These are useful to identify proteins and other molecules responsible for tumor growth.
One of the first strategies Dr. Knutson pursued was to try to identify biomarkers that could predict the clinical course of disease. The idea was to take immune cells from the blood of patients and see if the way they acted in a petri dish — their "immune signatures" — correlated with the future progression of their illness. Though Dr. Knutson ultimately wanted to use the approach in breast and ovarian cancers, he decided to do his first run in rheumatoid arthritis, an immune-related disease that he thought was bound to have some kind of immune signature.
Dr. Knutson teamed up with Dr. Gabriel, an epidemiologist, who for the past six years has been studying entire populations of individuals with rheumatoid arthritis. In some people, this illness is mild whereas in others it is aggressive, not only attacking their bones and joints but also other internal organs. Through her epidemiological studies, Dr. Gabriel found that people with rheumatoid arthritis experience an unusually high risk of heart disease, heart attack and heart failure.
Because sudden cardiac death is often the first cardiovascular event that someone with rheumatoid arthritis has, people don't realize they are at risk until it is too late, explains Dr. Gabriel. So, if researchers could develop predictive markers to identify those patients, they may be able to intervene and prevent devastating cardiac events.
Dr. Gabriel and her protege at the time, clinician-researcher John Davis, M.D., provided Dr. Knutson with hundreds of blood samples from their patients. Dr. Knutson isolated the immune cells and stimulated them with various immunity-stimulating chemicals to get a snapshot of what kinds of proteins — molecules such as cytokines, chemokines and the like — were released. The researchers eventually landed on a pattern of immune responsiveness that correlated with the early stages of heart failure (J Immunol. 2010). Their success so far demonstrates how being open to new and sometimes unorthodox collaborations can pay off.
"Before I started this project, I didn't know anything about Keith. I was just looking people up and knocking on doors to see who could help us take our research to the next level," says Dr. Gabriel. "The unique thing about Mayo is that somebody welcoming always seems to open the door, and it is just a matter of finding the right fit. Everyone is open to collaborating, and that is the way we do business — it is part of the culture here."
No more dead ends
An ovarian cancer tumor stained for regulatory T cells, which infiltrate and block immune responses against the cancer. Dr. Knutson's lab is seeking ways to stop the T cells from migrating into the tumor.
Just as a boosted immune system could be more effective in fighting cancer, an impaired immune response could make people more susceptible to the disease. Researchers have shown that ovarian cancer "escapes" the body's defenses by actively suppressing the immune system, but no one has ever linked that laboratory finding with patients' actual responses to treatment. And once women are diagnosed with ovarian cancer, there is wide variation in how people are affected, though it is not clear why.
Dr. Knutson joined forces with another epidemiologist, Ellen L. Goode, Ph.D., to test whether innate differences in women's immunity may be contributing to this variation. They are analyzing DNA and tumors from 800 women seen at Mayo Clinic, as well as 18,000 women internationally as part of the Ovarian Cancer Association Consortium, to see if inherited differences in immune genes can impact the clinical course of disease.
This summer the researchers will start crunching the enormous amounts of data that have accumulated from both projects. If they find genetic differences that relate to patient outcomes, they could be used to develop a genetic test to predict who would do better or worse on standard treatment. The findings could also give researchers biological insight into novel targets that could translate into better treatments for people with ovarian cancer. Dr. Goode says that the projects capitalize on an approach that is not only multidisciplinary, but "transdisciplinary," bridging across varied disciplines.
"We have realized that we need each other," says Dr. Goode. "We need other ideas, we need other methods, we need to make our work more applicable faster. We need to stop wasting time going down avenues that aren't going to end up doing anything for either public health or clinical care."
Dr. Knutson's training explains a bit of his prowess in spanning the bench and the bedside. After earning a Ph.D. in physiology and pharmacology from the University of Georgia, he did two postdoctoral fellowships — the first in basic immunology, studying the regulation of the immune response, and the second in translational immunology, helping clinicians evaluate the safety and effectiveness of cancer vaccines in breast and ovarian cancer.
"The fact that I have training at the bench and in clinical applications means that I can do research developing new immunologic strategies to understand and treat disease and then develop partnerships needed to move them into the clinic," said Dr. Knutson.
With bridge builders like Dr. Knutson on the job, those dead ends may become fewer and far between.