(Vienna, 21.09.2020) Priv.-Doz. René Geyeregger, PhD, is taking full risk on a promising research project. Because this is often the only way to create something groundbreaking. Something that helps children with cancer who no longer respond to current treatment. Geyeregger heads the Clinical Cell Biology and FACS Core Unit of the St. Anna Children's Cancer Research Institute. In an interview during Childhood Cancer Awareness Month September, he talks about how his path – not always straight – led into science. And what fascinates him so much about it, that he sticks to his ideas even when he has to overcome obstacles to pursue his goals.
What are you currently working on?
Three out of ten children suffering from osteosarcoma, a type of bone cancer, develop metastases after the first treatment. Metastases occur mostly in the lungs and a part of the lung can be resected surgically. However, in the long term, it is difficult to help these children. Since the 1970s there has been hardly any progress concerning new treatment options for these patients. We are now developing a truly new therapeutic approach that will support the immune system in its fight against this tumor. Results from other researchers indicate that our approach could work, even though no one has ever tried to verify this hypothesis before.
Could you please describe this new approach?
Mutations in the tumor cause tumor cells to carry certain signals on the surface. So-called neoantigens or other antigens that differ from those of healthy cells make the tumor vulnerable to an attack by the immune system. Although there are only a few such antigens in osteosarcomas, we have already been able to prove that they are presented on the tumor surface at all.
In comparison to osteosarcoma, melanoma cells, for instance, carry many more neoantigens on the surface, as there are more mutations. In these tumors, it was shown that it is possible to isolate neoantigens and stimulate the patient's immune cells with them. Afterwards, so-called "primed" defense cells, which are supposed to fight the tumor, are re-infused to the patient.
What are the next steps to explore this method in osteosarcoma as well?
Together with Johannes Huppa from MedUni Vienna, Michael Traxlmayr from the University of Natural Resources and Applied Life Sciences, BOKU, Vienna, and Dietmar Rieder, from Med Uni Innsbruck, we intend to take the following research approach: We want to identify and artificially reconstruct the T cell receptor that is located on the surface of certain immune cells, termed T lymphocytes, which migrate into the tumor and recognize tumor antigens (e.g. neoantigens). At the same time, we examine which neoantigens the tumor has on its surface, by applying sophisticated bioinformatic methods.
As soon as we have identified a T cell receptor, we use it to screen a library of yeast cells that present up to one billion different antigens. If, according to our computer simulation analyses, these are tumor-specific antigens, we try to verify this in cell culture and check whether the immune cells with the new receptor are able to kill the tumor cells.
So every child needs an individual therapy?
Yes, exactly, our new approach would always be tailored to the individual patient. Likely, it would take a certain amount of time for establishment. After two to three months you could ideally find the individual T cell receptor for each child. Then you should equip an army of T cells with this receptor and re-infuse them to the patient.
Which problems do you face in developing this therapy?
One problem is the hostile environment towards the immune system, in which the tumor is embedded. Tumors try everything to prevent them from being killed. For example, they shut down their receptors so that the T cell does not recognize them as wrong. We believe that what matters is the mass of suitable immune cells, fighting the tumor. If you attack it with billions of armed cells, at some point the tumor will not be able to escape anymore.
Second, we do not yet know for certain, whether the chosen T cell receptor(s) will be tumor specific. Also human leukocytes antigen (HLA) molecules are difficult to produce, leading to further open questions: Will we be successful with the HLA systems we use? Can we optimize the T cell receptor in a way, which makes him recognize tumor antigens specifically and exclusively?
If we ultimately manage to develop this therapy, we expect a high impact. However, it is also a high risk project. In addition, we also learn to understand the interaction of the immune system with the tumor much better.
What other research projects are you pursuing?
On the one hand, we are investigating the T cell immune response to the SARS-Coronavirus (CoV)-2, and among other things we want to find out which parts of the virus protein are specific for SARS-CoV-2 and which parts are specific for common cold, caused by harmless corona viruses. We want to develop a test with 100 percent specificity showing whether someone was infected with SARS-CoV-2 or not.
On the other hand, we want to develop an exact map of the immune reconstitution of T and B cells after stem cell transplantation. To achieve that, we combine multiparameter flow cytometry and single cell sequencing with the latest machine-learning tools.
However, only about one third of our work involves research activities. Another third is dedicated to diagnostics in children after hematopoietic stem cell transplantation, where the immune system has to be reconstituted. During this phase, we analyze the immune cells of patients and inform physicians which cells are present in which quantity.
The rest of the time, we spend on drug production in the Good Manufacturing Practice (GMP) laboratory. Unfortunately, we are not always able to plan when we have time for research, as rapid routine analyses or productions are often required.
Why did you choose to become a scientist?
After graduation from high school, I wanted to study Industrial Design to combine technology and creativity, but failed the entrance examination. Afterwards I briefly enrolled for business administration, followed by business informatics at the Vienna University of Technology. Both studies were very theoretical and boring.
A friend of mine studied biology with the focus on genetics. That seemed to be quite interesting. And indeed, already the first lecture fascinated me, so I enrolled genetics and finished my studies in a short period of time.
What was the next step?
During my diploma thesis, I was able to produce nanoparticles for drug targeting. Then I applied for a PhD position focusing on immunology, polyunsaturated fatty acids and their effect on immune cells.
Immunology has been extremely fascinating for me. I established innovative new techniques during the three and a half year lasting PhD position and developed my own projects. I had a lot of freedom to bring in my ideas and work on them. From this research period, high ranking publications resulted, which opened the doors to laboratories, where I could mainly focus on applied research projects.
How did you get into cancer research?
I applied at St. Anna Children's Cancer Research Institute and was selected for a senior post doc position at my lab back then. Some transplanted pediatric patients get a usually harmless adenovirus infection, from which they can die in their immunocompromised state. At the institute I was able to develop a new cell therapy up to the first clinical study phase. My former supervisor retired in 2017. After that, I took over his responsibilities as a group leader for both the research and diagnostics in our laboratory. I became managing director under trade law, head of the Fluorescence-Activated Cell Sorting (FACS) Core Unit and deputy leader of the GMP production.
In the meantime, I have completed a part-time university course to become a qualified person in order to be allowed to release cell products. Since August, I additionally study biomedical analytics.
Where does your motivation come from?
When I realized that I can improve the benefits for patients, I was filled with enthusiasm. Virus diagnostics, for example: Back then, there were no suitable methods to determine whether the patient had defense cells or not. We therefore established new solutions at our institute.
I am driven by the wishto develop something useful and applicable for the patient – of course considering all the regulatory necessities that this entails.
What do you particularly like about your job?
For example, when you succeed in a "compassionate use healing attempt" by the application of your newly developed method in a patient who is threatened to die of cancer or a virus because other therapies no longer work. That is something very fulfilling. The parents are desperate, they have tears in their eyes, and you are able to help them. I still get goose bumps when I think about it. It's very satisfying to work here. I always have the feeling that we are doing something meaningful for the patients and that drives me on. When I hear about the unfavorable fate of patients, I strongly wish to help them.
That's not always completely altruistic. Of course I also want to accomplish something for myself. But my work wouldn't fulfill me as much if I did straight basic research, for example. Therefore, what really drives me every day is: I want to develop something that helps patients.
Which qualities do you need to be successful in science?
I am very creative, which is something that benefits me here every day.
I am also convinced that you have to believe in your ideas. Besides that, I am very communicative and well connected to other scientists. This is of great importance, especially in present times! Working on your own you can't achieve anything anymore. The exchange with scientific colleagues is essential.
All further research portraits will be published online during the childhood cancer awareness month of September on our websites:
Priv.-Doz. René Geyeregger, PhD
Priv.-Doz. René Geyeregger, PhD, has been head of the Clinical Cell Biology and FACS Core Unit of St. Anna Children's Cancer Research since 2017, where he previously worked as a senior scientist and deputy group leader, respectively. Since 2017, Geyeregger has also been head of the good manufacturing practice (GMP) laboratory and managing director of Labdia-Labordiagnostik GmbH.
In 2016, Geyeregger received the venia docendi in the field of immunology at the Medical University of Vienna, where he continues to work as a lecturer. After his studies of biology (with main emphasis on genetics), he completed his PhD in genetics at the University of Vienna and the Medical University of Vienna. Further scientific stations were a post-doc position at the Department of Internal Medicine III and the Institute for Cancer Research at the Medical University of Vienna. Furthermore, Geyeregger completed postgraduate studies in Pharmaceutical Quality Management at the University of Vienna.
His research focuses on the improvement of diagnostics for the detection of virus-specific T cells (ongoing projects on SARS-CoV-2), the development of innovative adoptive cellular therapies (for osteosarcoma), diagnostics after hematopoietic stem cell transplantation and graft-versus-host disease.
For his research projects, Geyeregger received highly endowed grants, among others from the Austrian Research Promotion Agency (FFG) and the Vienna Business Agency. The scientist collaborates with international partner institutes such as the Dana-Farber Cancer Institute and the Hannover Medical School.
In addition, Geyeregger is reviewer for renowned journals, including Blood, Molecular Therapy and Gene Therapy. He is a member of various professional societies, including the Austrian Platform for Personalized Medicine (ÖPPM), the European Society for Blood and Bone Marrow Transplantation (EBMT) and the Austrian Society for Allergology and Immunology (ÖGAI).
Geyeregger was awarded the Novartis "Oral Challenge" prize for the best presentation as well as the Basic Science Award for the best publication at Austrotransplant annual meetings and received the poster prize of the Austrian Society for Allergology and Immunology (ÖGAI).
Osteosarcoma is a rare, usually very malignant bone tumor, which occurs predominantly in the second decade of life. About 70 percent of patients respond well to the first treatment. However, metastases form in about 30 percent, especially in the lungs. For the latter, there is currently a lack of long-term effective treatment methods.
Geyeregger and his team would like to develop a completely new form of therapy. It is difficult for defense cells to act against osteosarcoma because the tumor has established various methods to escape the immune system. However, some immune cells that are able to recognize the tumor specifically. With the help of modern molecular methods, the scientists aim to detect and examine these rare immune cells in the laboratory. Genetic modifications are to be used to make these cells "sharp" and thus enable them to react better against the tumor. If the method proves successful in the laboratory, patients could be re-infused with a large number of such modified immune cells in the future.
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