Introducing Angelika Riemer - Stimulating the Immune System to Fight Cancer

bridges vol. 26, July 2010 / News from the Network: Austrian Researchers Abroad

By Maria Hinnerth



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Angelika Riemer

For almost 300 years, there have been discussions of whether the immune system is capable of fighting cancer. The first indications that this might be possible were in the 18th century, when it was noted that feverish infections in cancer patients were occasionally associated with cancer remission. In the 1890s the New York surgeon William Coley began to seriously investigate this phenomenon. He discovered that an infection with the bacterium Streptococcus pyogenes caused a severe inflammation, which could lead to a remission of cancer. He injected heat-killed Streptococcus cultures ("Coley's Toxin") directly into the tumor tissue and observed regression in some cases. With this method, he could achieve a cure rate of at least 10 percent. Despite this success, many scientists believed that it would be impossible for the immune system to recognize and respond to its own malignant cells. It took almost 100 years and the persistence of visionary scientists like Lewis Thomas and Sir MacFarlane Burnet, who enunciated the "Tumor Immunosurveillance Theory" to reach the present awareness that the immune system IS capable of fighting cancer. This knowledge is now utilized for the development of cancer vaccines, and the Austrian Angelika Riemer is among the top researchers worldwide in the field of cancer vaccination.

Born in Salzburg in 1976 as the oldest of three girls, Riemer already knew as a teenager that she didn't want a nine-to-five job for her professional life, but something more challenging. Thanks to her brilliant intellect, her encouraging family - which always affirmed that there is nothing a girl can't do - and her excitement about learning new things, she made her way through her medical studies with excellent grades and finally graduated sub auspiciis. Only a graduate who achieves an A average from high school through the achievement of a doctoral degree is honored sub auspiciis. As she first came in contact with immunology in the course of a pathophysiology lecture, she was intrigued by the subject and knew that this was the field in which she wanted to do research. This was the reason that Riemer chose to take an undergraduate course in immunology during her exchange semester at the Monash University in Melbourne, Australia. There she had to write a final paper and, out of several different topics to choose from - and even back in 1999 - she chose cancer vaccines. But why was she so fascinated by immunology and cancer vaccines in particular? She explained it as follows: "I really believe that there is a lot to be achieved if we learn enough about the immune system to stimulate it into eradicating cancer. Research in this area is fascinating and also satisfying. More and more people suffer from cancer and if you just imagine that one day you could help them through vaccination! I think it is a rewarding field of research."


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In 2008, according to the WHO, 12.7 million new cancer cases were diagnosed and 7.6 million people died of cancer: more than HIV/AIDS, malaria, and tuberculosis combined. By 2030, the number of cancer deaths is expected to rise to 12 million and the cancer incidence will rise to 21 million.
As promising as research into cancer vaccines may seem, one always has to keep in mind that cancer developed although the immune system was present. Day-to-day, our body is confronted with combating numerous pathogens and eliminating already damaged cells. Pathogens can invade the body through several different ways such as contact with aerosolized droplets spread by sneezing, coughing, talking, or kissing, or through direct contact with contaminated surfaces. The first layers of defense against these pathogens are the surface barriers of the body, like body fluids or our skin. However, if a pathogen still manages to enter the body, it will encounter the cells and mechanisms of the so-called innate immune system - a general, non-specific defense mechanism, triggered when invaders are identified by recognition receptors or when damaged or stressed cells send out alarm signals that recruit immune cells to sites of infection. In addition to these general defense mechanisms, the innate immune system is also responsible for the activation of the adaptive immune system through a process known as antigen presentation (for an animation about antigen presentation click here). The adaptive immune system enables a stronger immune response and an immunological memory. This means that after a first infection, the resultant antibodies and specific memory cells remain in the body and enable a quicker immune response if an infection with the same pathogen takes place again.

 

Cancer has some strategies to evade the immune system. Cancer cells are the body's own tissue and are therefore protected from immune response by various mechanisms like self-tolerance or the secretion of immunosuppressives. "This is why I chose to work with Human Papilloma Virus (HPV)", Riemer says, "the virus leaves antigens within the cancer, which mark the cancer cells as foreign and therefore it is easier to target them." Another problem with cancer vaccines at the current stage of research is that they only work for small lesions. They have to be administered at a very early stage or after surgery when just a few cells of the tumor are left.



Different types of cancer immunotherapy


Through immunotherapy, scientists try to take advantage of the abilities of the immune system in order to use the body's self-healing power to fight diseases. One way to achieve that is through vaccination. There are therapeutic vaccines, such as the recently approved Provenge, intended to treat already existing cancer. Beside these, there are prophylactic vaccines, like those that prevent HPV infection, which prepare the body to resist infection by a certain pathogen by simulating an infection with a harmless vaccine. A common factor in both types of vaccination is that they are an active immunization, which means that they trigger an immune response and induce the development of a long-term immunological memory. In contrast, passive immunization has an immediate effect. Large amounts of specific ready-made antibodies are administered, which helps the body to fight the disease but doesn't have a long-lasting impact.

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Throughout her scientific career, Angelika Riemer has worked on developing active tumor immunotherapy. Her first scientific work on cancer vaccines was her 2001 doctoral dissertation, Development of a Mimotope Vaccine against Malignant Melanoma, on research that she carried out in the laboratory of Erika-Jensen-Jarolim, head of the Institute of Pathophysiology at the Medical University of Vienna . Besides her scientific research work, Riemer began her first specialist training in immunology in 2001. "I never considered working anywhere else than at a university hospital because there you have the possibility to combine research and working as a doctor."

Riemer's scientific work at the University of Vienna was focused on the development of so-called epitope-mimic or mimotope vaccines; a mimotope is a very small protein, which structurally mimics the antibody-binding site on an antigen. The vaccine works by the "lock and key" principle. When an antibody recognizes the antigen against which it is directed, they fit together like a key in a lock. So when a patient receives the vaccine, an immune response is elicited and the antibodies produced target the antigen mimicked by the mimotope. In her first doctoral dissertation Riemer intended to develop a mimotop vaccine, which was capable of inducing anti-melanoma-antibodies. Indeed, after vaccination antibodies were produced but the anti-cancer effect was relatively low. Nevertheless this kind of vaccination has many advantages - for example, mimotopes can be produced easily on a large scale. Furthermore, there is no infectious material involved, so it is quite safe. The mimotopes generate a preset type of immune response and can be coupled to immunogenic carrier molecules in order to boost immunogenicity.
 

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Austria's Federal President Heinz Fischer applauding Angelika Riemer.

Riemer's second doctoral dissertation also dealt with the analysis of mimotopes.  She discussed the question of how to create mimotopes that trigger antibodies that block growth-stimulating proteins on certain breast cancers. In 2005 Riemer finished her second doctoral degree, again sub auspiciis. So far, only five people in Austria have achieved two sub auspiciis graduations. Subsequently, she was given an ad personam position at the Medical University of Vienna for her second specialist training in dermatology, meaning that this position was created just for her. In 2007 she qualified as a professor of immunology with her habilitation, From passive to active tumor immunotherapy: Mimotope vaccination for epitope-specific induction of trastuzumab-like anti-Her-2 antibodies.

Mimotope vaccines are a promising tool for the future of cancer immunotherapy but their development is still in its early stages. Many cancer treatment vaccines are in clinical trials and, hopefully, some of them will make their way to the market. The very first therapeutic cancer vaccine that enables an active immunization was just approved by the US Food and Drug Administration (FDA) on April 29 this year. Called Provenge, it is applied in men with advanced prostate cancer. It is manufactured by isolating a patient's dendritic cells from their blood. The cells are then exposed to a protein found in most prostate cancers, linked to an immune-stimulating substance. After this procedure, the cells are returned to the patient intravenously. Provenge was shown to improve survival by about four months. "The challenge with Provenge is that you don't have one vaccine for anyone. Each patient has to be given his individual vaccine made from his own immune cells. It is a very elaborate process," Riemer explains.

Beside therapeutic vaccines, which are intended to treat cancer, there are prophylactic vaccines, intended to prevent certain cancers from developing. To this day, HPV- and Hepatitis B virus vaccines are the only approved prophylactic cancer vaccines. Chronic hepatitis B virus infection causes about half the world's liver cancer deaths, killing 340,000 people annually. But vaccinating children can protect against the virus and prevent liver cancer. In Taiwan. all newborns have been vaccinated with the HBV vaccine in a nationwide vaccination program implemented in 1984. Since then, the average annual incidence of hepatocellular carcinoma in children 6 to 14 years of age declined from 0.70 per 100,000 children between 1981 and 1986 to 0.36 between 1990 and 1994.


From Harvard to Heidelberg

After having received all possible academic accolades in Austria, Angelika Riemer knew that it was time to further her education abroad - destination Harvard Medical School . "In research everybody always talks about the United States; that everything is so great there and the opportunities are just amazing," Riemer explains, "and I wanted to see that for myself. The decision to go to Harvard obviously was ‘why not try at the top'. In addition, it is more likely to get funding at the top institutions."

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Nobel Prize winner Harald zur Hausen.

Riemer received an Erwin-Schroedinger scholarship and started working as a scientific research fellow at the Dana-Farber Cancer Institute in January 2008. She was working at the Cancer Vaccine Center under the leadership of Ellis Reinherz , who is famous for revealing key functional and structural information about T-cell receptors, which is crucial to the development and design of cancer vaccines. Riemer focused her research at Harvard on a cancer treatment vaccine that addresses cancer caused by HPV. This has been professionally challenging for her, as she changed from working on breast cancer to HPV and also changed from mainly working with antibodies to working with immune cells, so had to learn lots of new techniques. During her literature research on HPV she often came across the Nobel Prize winner Harald zur Hausen , who discovered that cervical cancer is caused by HPV. To Angelika Riemer, zur Hausen is the equivalent of a scientific dream story. "You know, when he started he was laughed at by the scientific community. For 10 to 20 years nobody believed him but he persevered and was proven right." In the 1980s zur Hausen and his collaborates had already identified HPV16 and HPV18 in cervical cancers, but it took until 2006 to release a HPV vaccine. The principle of this vaccine is to stimulate the body to elicit virus-neutralizing antibodies by injecting HPV virus-like particles, which are non-infectious. The neutralizing antibodies bind the virus before it reaches its target cell. More than 250,000 women die annually from cervical cancer, 99 percent caused by HPV, and WHO projects that cervical cancer deaths will rise to 435,000 in 2030. Seventy percent of cervical cancers are caused by these two types of virus (HPV16 & 18) which the vaccine protects against. But because the virus is intracellular after an infection and no longer accessible to the antibodies, the HPV-vaccine is only effective in people who have not yet been exposed to HPV.

Because Riemer was so impressed by zur Hausen, she attended a talk he gave in Boston. After his talk she went up to him, introduced herself. and told him what an honor it was to meet him. Later on they met briefly at a conference in Salzburg, and afterwards Riemer was invited to a symposium in Heidelberg. On the first evening there, even before the symposium took place, zur Hausen came over to her and asked if she wanted to become a group leader at the German Cancer Research Center . Riemer was stunned. She asked him: "Why did you chose me?" and he told her: "Well, I liked you and then I googled you and I liked what I found even more!"

On July 1 this year, Riemer started her work in Heidelberg and is absolutely thrilled about it. "The position is like the typical American start-up package. There is funding for five years for me, three employees: one post doc, one PhD student, one technician, and of course money for materials." And she can even continue her specialist training in dermatology along with her research work. Since her research work in Boston has been taken into account she already finished her first specialist training and is now a medical specialist for immunology. In the lab, Riemer focuses on development of a T-cell-inducing vaccine, which will hopefully lead to a vaccine that could be broadly applicable. Compared to the existing prophylactic vaccination, such a vaccine would help people who already have an HPV infection to get rid of it.

"My plan is just to really try and make the most out of this incredible chance. I think if the concept works in HPV, a lot will be learned about generating cancer vaccines. Five years ahead is such a long time in science. So much can happen. I'll see where it leads me."

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The author, Maria Hinnerth, holds a master of science in biotechnology from the University of Natural Resources and Applied Life Sciences, Vienna. 



Sources & References:


Chan, M.H., et al "Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group." The New England Journal of Medicine 336(26), (1997): 1855-59.

Parish, C.R. "Cancer immunotherapy: The past, the present and the future." Immunology and Cell Biology 81, (2003): 106-13.

Riemer, A.B. "Impfstoffe gegen Krebs." Spectrum Dermatologie 2, (2009): 44-6.

Riemer, A.B., Jensen-Jarolim, E. "Mimotope vaccines: Epitope mimics induce anti-cancer antibodies." Immunology Letters 113, (2007): 1-5.

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