Scientific Concept
Recent breakthroughs in the field of immunology research have greatly extended our knowledge not only about the role of immune cells in infection, allergy, autoimmunity and cancer, but also on how the immune system is shaped by tissue environments or the microbiome, and how it contributes to normal tissue homeostasis and repair.
Translation of these fundamental immunobiological processes into clinical application will leverage novel immunotherapies (e.g. targeted delivery of mRNA compounds or genetically modified T cells) across a much broader spectrum of diseases. At the same time, the use of novel immunotherapies continues to trigger novel research questions, paving the way for new therapeutic targets (reverse translation). For example, the advent of immune checkpoint inhibitors, such as PD-L1-blocking antibodies, has revolutionized cancer immunotherapy. However, it is also evident that many patients derive only transient benefits and significant immune-mediated side effects from these treatments, highlighting the need for a deeper patient-oriented understanding of immune-mediated diseases and immune interventions.
The translational research network at the UMC provides an excellent basis to address questions as such by a close collaboration between clinicians and immunobiologists.
The following four areas of unmet medical needs will be addressed in the ACTIVATE program:
1. Predictive biomarkers for disease activity, response to therapy and disease prognosis:
Currently, immune dysfunction cannot be thoroughly assessed in diseased patients.
Only few auto-antibodies and acute-phase proteins serve as biomarkers in routine clinical practice, and immunohistochemistry is typically limited to two or three parameters on a tissue slide. Molecular diagnostics are only applied in a limited number of diseases, and few imaging techniques are available to visualize immune activation sites in patients. To enable precise therapeutic interventions, we need more specific serum biomarkers, multi-parameter high-resolution assessments of cells and tissues, and improved functional imaging techniques to understand immune dysregulation and immune activation. Furthermore, systematic molecular data on disease progression in patient
cohorts, combined with serum and tissue analyses, is essential.
2. Therapeutic options for individualized immunotherapy:
Although immune-mediated diseases are characterized by unique, patient-specific, and disease-specific immune pathologies, most patients are still treated with corticosteroids or other non-specific immunosuppressants that are not tailored to target specific antigens or immune cell types. As a result, these treatments affect the immune system as a whole, leading to significant side effects such as infections, metabolic changes, or organ/tissue damage. Furthermore, few therapeutic options are available for immune activation (e.g., immune checkpoint inhibitors), which act non-specifically on multiple immune cell types and are not antigen-specific. This can result in unwanted immune activation against healthy tissues, sometimes leading to life-threatening autoimmune side effects. Therefore, there is an urgent need to develop antigen- and disease-specific, patient-tailored treatments.
3. Understanding of immune dysregulation mechanisms in tumor tissue:
Albeit increasing knowledge, the pathophysiology of tumor-immune-interactions remains incompletely understood, particularly regarding the complex interplay of cellular components and soluble mediators within the tumor microenvironment. A deeper understanding of these dysregulated interactions requires innovative (murine) disease models that can be precisely manipulated, access to diseased patient tissues, advanced single-cell analytical techniques including spatial transcriptomics, as well as systems immunology approaches including mathematic modelling.
4. Understanding of immune dysregulation in chronic inflammatory diseases:
Beyond cancer, infection, allergy and auto-immune diseases, there is a clear medical need to develop immunotherapies in novel areas such as cardiology, metabolic disorders, neurology, psychiatry or surgery, where chronic inflammation, dysregulated coagulation cascades and degenerative processes cause tissue damage that might be reversible or preventable by therapeutic immunomodulation.
