Interview Prof. Dr. Florian Kühnel

Interview with Prof. Dr. Florian Kühnel, Department of Gastroenterology, Hepatology and Endocrinology, MHH

What is your research aim and what are your main research questions?
Our aim is the development of oncolytic viruses for immunotherapy of solid tumors such as pancreatic or liver cancer. At the core of these immunotherapies are adenoviruses that we have genetically modified to preferentially infect and destroy cancer cells. Our research efforts are required to understand how oncolytic viruses, tumors, and the immune system interact and how limitations can be overcome by practical solutions to exploit the potential of oncolytic virotherapy. There are several research questions related to our aim. In order to reduce unwanted side effects, we modify our viruses in such a way that viral replication is suppressed in healthy cells. We also work at the surface of the virus capsid or use adapter proteins to improve infection of tumor cells.
An important task in oncolytic virotherapy is raising immune responses against the tumor. To this end, we equip viruses with immunostimulatory cytokines and T-cell activating proteins.

What are findings you are excited about? And what are your own major recent findings?
It is an exciting observation that oncolytic viruses have multiple immunological effects on tumor tissue and ‘unmask’ the tumor, making it easier for the patient’s immune system to recognize and fight it. Immune cells are raised with the ability to kill tumor cells with the potential to exert long-lasting antitumoral activity. In this regard, oncolytic viruses not only offer a huge potential for further technological advancement but also provide synergies with other immunotherapies.

One of our major findings recently concerns the antibody response against oncolytic viruses, which inactivates the virus and reduces therapeutic efficacy. We found that these antibodies can be repurposed for an antitumor attack by using recombinant adapter proteins. This study and further recent publications reflecting our work are listed below.

What kind of techniques and methods do you use for your research?
We do a lot of genetic engineering and have cell culture-based methods at hand to characterize our viruses regarding their ability to infect and destroy tumor cells. We also analyze signaling molecules released by dying tumor cells in order to understand the communication with immune cells. Finally, we want to know whether our generated viruses actually provide a therapeutic benefit. We use state-of-the art in vivo models for studying the efficacy of tumor infection as well as the strength of antitumor immune responses and their therapeutic impact.

How can translational research activities benefit from the CCC-N research structure?
I am convinced that translational research activities will greatly benefit from the CCC-N. The close cooperation of the participating medical institutions in Lower Saxony, including the two large medical universities in Göttingen and Hannover, provides a great opportunity to collaborate by sharing sample collections, knowledge and technologies. The CCC-N will also increase the visibility of the participating researchers and will thus certainly help to attract more funding to achieve translational research goals.

Can you tell us a little about yourself and your working group?
The oncolytic virus group at the MHH was started almost two decades ago and has been active ever since. Currently, we are eight members in total. We have a highly experienced and dedicated core staff consisting of one senior scientist (a veterinarian) and a technician. Furthermore, three talented PhD students of diverse educational background (e.g. biochemistry or biomedicine) are working on their theses. Two enthusiastic MD students are completing the group. Occasionally, we have students on board who work on their master thesis or do lab internships. My motivation to become a researcher has always been to find practical solutions using bioengineered viruses and proteins for future tumor therapies. This motivation was supported by excellent mentors and their encouraging attitude.

How can patients benefit from your research?
First generation oncolytic viruses have already been approved or are approaching the clinical stage, but the technology still offers much room for further improvement. We are aiming to participate in this development with our own viruses and therapy concepts. However, translational development of such a complex technology is a true challenge not only scientifically, but also regarding regulatory requirements and the financial dimensions that are needed. At least, we want to contribute to the research field by our efforts and ideas thus helping to bring the technology forward for the benefit of patients.

What is the biggest challenge in cancer research?
The biggest challenge in cancer research is the enormous diversity of tumors and their heterogeneity. Though prominent molecular players driving carcinogenesis are already well known, tumors are highly individual regarding their molecular characteristics and structural composition. Discovery of novel tumor therapies is therefore a challenging and time-consuming step-by-step process.

September 2022

Publications

Molecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy.
Niemann J, Woller N, Brooks J, Fleischmann-Mundt B, Martin NT, Kloos A, Knocke S, Ernst AM, Manns MP, Kubicka S, Wirth TC, Gerardy-Schahn R, Kühnel F.
Nat Commun. 2019 Jul 19;10(1):3236. doi: 10.1038/s41467-019-11137-5.

Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer.
Brooks J, Fleischmann-Mundt B, Woller N, Niemann J, Ribback S, Peters K, Demir IE, Armbrecht N, Ceyhan GO, Manns MP, Wirth TC, Kubicka S, Bernhardt G, Smyth MJ, Calvisi DF, Gürlevik E, Kühnel F.
Cancer Res. 2018 Jan 15;78(2):475-488. doi: 10.1158/0008-5472.CAN-17-2415.

Targeting polysialic acid-abundant cancers using oncolytic adenoviruses with fibers fused to active bacteriophage borne endosialidase.
Martin NT, Wrede C, Niemann J, Brooks J, Schwarzer D, Kühnel F, Gerardy-Schahn R.
Biomaterials. 2018 Mar;158:86-94. doi: 10.1016/j.biomaterials.2017.12.008.