An initiative of the Vienna Science and Technology Fund (WWTF) will enable the interdisciplinary team of researchers led by Dietmar Herndler-Brandstetter (Institute of Cancer Research), Michael Bergmann (Department of General Surgery) and Matthias Farlik-Födinger (Department of Dermatology) to push ahead with the development of novel immunotherapies for colorectal cancer. The project is entitled "Innate immune reprogramming to overcome therapy resistance in high-risk colorectal cancer", is funded to the tune of €800,000 and will run until November 2024. The three researchers are members of the Comprehensive Cancer Center (CCC) of MedUni Vienna and University Hospital Vienna.
There is an urgent need for new therapeutic approaches in metastatic colorectal cancer: the disease is the third most common cancer in both men and women, and, in 25% of patients, is not diagnosed until it has reached the metastatic stage. Only 14% of patients survive for longer than 5 years after diagnosis. On top of that comes the fact that 95% of those treated fail to respond to the currently approved immunotherapies.
New therapeutic approach: phagocytes
The innovative and interdisciplinary research project of Herndler-Brandstetter (coordinator) Bergmann and Farlik-Födinger therefore concentrates on the development and preclinical testing of novel immunotherapies using innovative sequencing and screening methods. The work focuses on the reprogramming of the innate immune system, more specifically of macrophages, the scavenger cells of the immune system.
Tumours are able to bind macrophages to them via the surface receptor SIRP alpha, thereby inhibiting these macrophages. Furthermore, they are able to alter macrophages that migrate into the interior of tumours, in a variety of ways. As a result of this, the phagocytes not only lose their ability to eliminate the mutated cancer cells, but also help to suppress the immune response to the tumour by preventing other immune system cells from fighting it.
How tumours alter macrophages
In their project, the researchers want to better understand which tumour subtypes are especially successful in modifying macrophages and why. This can then be used as a basis for developing novel strategies for precision diagnostics, reprogramming macrophages and overcoming immunotherapy resistance. The long-term goal is to test the findings in clinical trials on colorectal cancer patients.
Methods that are central to the project include the construction of special mouse models, for example so-called patient-derived tumour xenografts in mice with human immune system (Herndler-Brandstetter), innovative sequencing and screening methods (Farlik-Födinger), and the performance of multiplex immunohistochemistry (Bergmann).
The Vienna Science and Technology Fund (WWTF) was set up in 2001 to promote cutting-edge research in Vienna and to make the city attractive to international scientists. The private non-profit funding organization supports larger scientific projects that offer medium- to long-term economic and/or social benefits. The funding primarily covers staffing costs, but also investment, networking and overhead costs. The potential project term ranges from two to four years. The amount of funding can be up to 1 million euros, depending on the call.
The WWTF has been promoting life sciences since 2003 and, in recent years, has launched two major calls focussing on precision medicine. In the "Precision Medicine 2020" call, the allocated €6 million were quickly exhausted due to the high quality of applications. This colorectal cancer project was also judged to be excellent. The international funding jury therefore recommended that the WWTF should fund it. This has now been achieved: €350,000 came from three private foundations and this amount was doubled by the City of Vianna's Matching Funds, the residue being provided from the WWTF's own funds.
About Dietmar Herndler-Brandstetter
Dietmar Herndler-Brandstetter studied pharmacy at the University of Innsbruck. As a PhD student and FLARE Postdoctoral Fellow he worked at the Institute for Biomedical Ageing Research in Innsbruck and at the University of Birmingham (UK). As an Erwin Schrödinger Postdoctoral Fellow, he developed and characterized novel humanized mouse models for translational cancer research and for cancer immunotherapy in the laboratory of Richard Flavell (Yale School of Medicine, USA). In 2018, he moved to the Institute of Cancer Research at MedUni Vienna as a junior group leader. Together with his team, he is investigating how patient tumour heterogeneity and different immunotherapies shape the tumour-immune microenvironment and influence tumour growth and metastasis. Dietmar Herndler-Brandstetter has published more than 40 papers in journals such as Immunity, Nature Immunology, Gut, PNAS and Cell Host & Microbe and has received the Karl Landsteiner Award from the Austrian Society for Allergology and Immunology for his work on how aging affects immune-system function. He is also a member of the Comprehensive Cancer Center (CCC) of MedUni Vienna and University Hospital Vienna.
Website: Dietmar Herndler-Brandstetter - WWTF LS20 Project
About Michael Bergmann
Michael Bergmann studied medicine at MedUni Vienna. Following a postdoctoral fellowship at Mount Sinai Medical School, New York, on the genetic modification of the influenza A virus, he completed his training as a specialist in general surgery at MedUni Vienna, where he became Associate Professor of Surgery in 2003 and specialised in colorectal and robotic surgery. In addition to his clinical career, Michael Bergmann established a translationally oriented research group. He established the first oncolytic influenza A virus and generated stable influenza virus vectors, contributed to the understanding of the Toll-like-3 receptor signalling pathway for apoptosis during viral infections, and described the influence of retrotransposons on telomere regulation in cancer cells. In the field of clinical cancer immunology, he designed prospective study protocols for investigating immune checkpoint inhibitors during radio-chemotherapy for rectal cancer. He is currently investigating the effects of radiotherapy on the tumour microenvironment, the impact of Immunoscore© on the efficacy of chemotherapy in colorectal cancer, and the value of nuclear imaging for detecting immune checkpoint molecules in gastrointestinal cancer.
Michael Bergmann is a member of the management team at the Comprehensive Cancer Center (CCC) of MedUni Vienna and University Hospital Vienna.
About Matthias Farlik-Födinger
Matthias Farlik-Födinger studied microbiology and genetics at the University of Vienna and completed his PhD in the laboratory of Thomas Decker, where he worked on gene regulation processes leading to the activation of antimicrobial genes in macrophages during infections. As a postdoctoral researcher, he worked in Christoph Bock's team at the Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM). Working closely with bioinformaticians, he developed and established new sequencing technologies for the epigenetic characterization of cells in an interdisciplinary environment with the aim of understanding the development of both healthy and diseased cells. He also works closely with clinical researchers to identify the original cell type and molecular basis of cancer progression in rare macrophage-driven diseases. In 2019, he was appointed junior group leader at the Department of Dermatology, Medical University of Vienna, and became head of the laboratory for the study of INnate IMmune ACtivation (INIMAC). He and his team use state-of-the-art technologies to investigate the role of innate immune cells, such as macrophages and natural killer cells, in shaping the tumour microenvironment and in responding to infectious diseases. His work has led to much-cited publications in scientific journals such as Science, Cancer Discovery, Immunity, CellStemCell and Molecular Cancer. His doctoral thesis won him the prestigious "Award of Excellence" from the Austrian Ministry of Science as well as the "Ursula and Fritz Melchers Prize" from the Austrian Society for Immunology and Allergology. He recently received the "Research Award of the Austrian Society for Biotechnology" and the "MEDA Award" of the Austrian Society for Dermatology and Venereology for research into non-melanoma skin cancer. Matthias Farlik-Födinger is also a member of the Comprehensive Cancer Center (CCC) of MedUni Vienna and University Hospital Vienna.