8 minute read
11 Research Networks
11
Research Networks
Our department cooperates with numerous partners in Zurich, in Switzerland and abroad. Our collaborative networks combine innovative clinical oncology and hematology, research, technologies and medical bioinformatics to develop novel diagnostic and therapeutic concepts.
Hochschulmedizin Flagship Project: Immuno-TargET
Lead-PIs: Felix Beuschlein (Endocrinology, Diabetology and Clinical Nutrition, USZ), Markus G. Manz (MOH) Keywords: Immmunotherapy, Autoimmunity, neuroendocrine Tumors
ImmunoTargET aims to transform pathologic mechanisms of autoimmunity into efficient tools to fight cancer of endocrine organs.
Autoimmune diseases and cancer have highly interesting parallels that can be used for novel therapeutic approaches. Tumors that originate from endocrine (hormone-producing) organs, such as the thyroid gland, the parathyroid gland, the pituitary gland or the gastrointestinal tract, are often characterized by excessive hormone production and frequently retain the functional and molecular properties of their originating organ. Of the much more common autoimmune diseases against endocrine organs (e.g. type 1 diabetes, autoimmune thyroiditis), it is known that the body’s own antibodies often completely destroy hormone-producing cells. This principle is used to attack endocrine tumors with specific immunotherapies. Immuno-TargET aims to isolate and characterize autoimmune effectors and antibodies and transform them in anticancer agents via the generation of multispecific T-cell activators and CAR immune effector cells such as CAR T-cells.
Graphical abstract of the project
The LOOP Zurich: INTeRCePT – Intercept clonal evolution to overcome treatment resistance in childhood and adult blood cancer
PIs: Thorsten Zenz (MOH), Burkhard Becher (UZH), Nico Beerenwinkel (ETHZ), Jean-Pierre Bourquin (University Children’s Hospital Zurich /UZH), Wolfgang Huber (EMBL), Andreas Moor (ETHZ), Berend Snijder (ETHZ) Keywords: Blood Cancer, Treatment Resistance, Molecular Profiling
Precision medicine for blood cancer patients: We investigate the biomolecular reactions in ultra-high resolution at the level of individual cells. This will help us understand the heterogeneity of tumor and normal immune cells, and their interactions.
Patients with lymphoma or acute lymphoblastic leukemia who do not respond to treatment have a bleak outcome. Over 1.100 patients die with leukemia and lymphoma in Switzerland annually, despite a diverse treatment landscape. There is a major need to optimize treatment selection for patients with blood cancer. To improve the outcome of lymphoid malignancies in children and adults, we will channel relapsing blood cancer patients in Zurich into a new Innovation Clinic. Treatments are applied, often multiple times consecutively, and each time tumors and normal blood cells are collected before treatment. In laboratory experiments, we determine the precise molecular state as well as the dynamic response of these collected tumor samples, at multiple levels of their molecular biology and at single-cell resolution. The drugs will include all drugs potentially available for treatment, including those used in the patient. By computational analysis, we construct a detailed single-cell map of drug response and use this to derive a broadly applicable procedure aimed at extinction of the tumor (INTeRCePT), which we test in a trial, aiming to increase response rate by 50%.
Graphical abstract of the project
Lead-PIs: Thorsten Zenz (MOH), Jean-Pierre Bourquin (University Children’s Hospital Zurich) Keywords: Precision Medicine, Drug Response Screening
The CRPP “Precision Hematology / Oncology” joins forces to develop a clinical platform for next-generation precision medicine. We aim to apply drug response profiling to personalize treatment of patients and investigate unexpected vulnerabilities at depth.
Despite rapid progress in cancer genomics and molecular disease classification, it remains difficult to identify actionable targets and predict response to drugs based on this information. New approaches that identify cancer vulnerabilities and predict the response to treatment based on pre-treatment testing of individual cancer cells could improve response rates, reduce unnecessary treatments, and significantly increase cost-effectiveness. Based on strong proof-of-concept data, the CRPP hypothesizes that critical predictive and mechanistic information can be obtained from direct functional drug response screening of primary patient samples.
Graphical abstract of the project
Clinical Research Priority Program (CRPP): ImmunoCure – Targeted Cancer Immunotherapy
Lead-PIs: Patrick Roth (Neurology, USZ), Markus Manz (MOH) Keywords: Engineered Immunotherapy, T-cell Engagers and Activators, Car-T Cells and NK-Cells
ImmunoCure focusses on novel, “engineered” immunotherapeutic concepts such as T cell engaging and activating bispecific antibodies (TEA) as well as CAR-T cell and CAR-NK cell therapy.
Immunotherapy represents a key promising area of novel therapeutic approaches against cancer. The CRPP ImmunoCure aims at establishing and expanding the concepts of T cell engaging and activating antibodies and CAR-T cells as cornerstones of a “targeted therapy development and technology immunotherapeutic platform” in Zurich that includes (i) monoclonal antibody engineering, (ii) CAR cell engineering, (iii) in vivo modeling and 3D imaging of (CAR) T cell traveling and target cell killing; and (iv) profiling of immune cell responses. ImmunoCure will explore these technologies in two “targeted therapy lead disease focus programs”, one on brain tumors and one on hematologic stem cell malignancies as acute myeloid leukemia and myelodysplastic syndromes.
Graphical abstract of the project
Tumor Profiler Center
Lead-PIs: Andreas Wicki (MOH), Bernd Bodenmiller (UZH/ETH), Viola Heinzelmann (University Hospital Basel) Keywords: Oncology, Precision Medicine, Therapy Prediction, Functional and Multi-Omics Testing
The Tumor Profiler Center (TPC) is a cancer-specific research consortium and competence hub of the universities (UZH, ETH) and university hospitals in Zurich.
State-of-the-art high throughput platforms are used to assess tens of thousands of biomarkers from solid or liquid samples within the time-frame of two weeks. Data is used for support of therapy decisions at the molecular board (fast diagnostic loop) and mined through machine-based learning and artificial intelligence for diagnostic, prognostic and predictive information (exploratory loop). The TPC supports both the MOH Personalized Oncology Program, and the Swiss-wide Precision Oncology Program (SPO) of the Swiss Personalized Health Network. From 2018 to 2021, patients with melanoma, ovarian cancer and acute myeloid leukemia (AML) were included and analysed by TPC. From 2022 to 2025, additional cohorts of patients with breast cancer, lung cancer and colorectal cancer will be activated and recruit patients.
Within the frame of TPC, MOH coordinates the AML TuPro project (PIs: Alexandre Theocharides (MOH), Markus G. Manz (MOH), Berend Snijder (ETHZ)). The project uses an unbiased multiomics approach to identify therapeutic vulnerabilities in AML patients with relapsed/refractory disease (RR AML), which is characterized by poor outcome. Samples from RR AML patients are analyzed with different high-throughput technologies provided by TPC. In particular, the AML TuPro uses two drug screening platforms where the response of AML patient cells to >80 different compunds is assessed ex vivo. This data is then correlated to DNA and RNA sequencing data and to proteomics data. This approach also supports the identification of biomarkers that may predict the response to therapies. The integrated data will be discussed in tumor boards to select personalized therapies for RR AML patients. The overall aim is to increase our understanding of the mechanism of therapy resistance and to ultimately develop new therapeutic strategies.
Several tens of thousands of biomarkers can be assessed from each tumor sample within two weeks. They contain information on the vulnerabilities of a tumor and can be mined for information on potential drug targets and best treatment strategy.
A Wyss Zurich project: Phire – Antibody-enabled blood stem cell transplantation
The interdisciplinary team of the Wyss Zurich Phire project consists of scientists, engineers and medical doctors from ETH Zurich and University Hospital Zurich/University of Zurich. Mentors: Markus Manz (MOH), Dario Neri (Philogen) Keywords: Antibody, AML, Precision Medicine
Phire aims at the development of a novel bispecific T-cell engaging antibody in order to transform current HSCT practice into an immunologic precision-medicine approach. Hematopoietic stem cell transplantation (HSCT) is a powerful intervention to cure life-threatening diseases of the blood and immune system, such as Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS).
For a successful transplant of blood stem cells, the patient’s own, faulty blood system needs to be removed to make room for donor stem cells and to ensure engraftment and regeneration of the donor hematopoietic system in the patient’s body. Removing the patient’s own, faulty system is the first step of a transplant and is called `conditioning phase`. Today, this conditioning phase is being performed through intensive chemotherapy and in some cases radiation – both with severe side effects. These side effects prevent the majority of elderly and frail patients from receiving a transplant. In order to establish the new therapeutic paradigm, Phire will initially focus on treating patients with AML and high-risk MDS. However, if successful, the bispecific antibody might revolutionize the way HSCT is performed, with a potential benefit not only for the treatment of AML and hrMDS, but also for a variety of other hematological conditions. This means that our approach might enable “Regenerative Medicine” on a grater scale. In theory, every patient with a faulty blood system, that could be cured by removing, replacing and regenerating the hematopoietic system could benefit from our enabling technology.
Graphical abstract of the project
PIs: Amyloidosis: Rahel Schwotzer (MOH), LCH: Wiebke Rösler (MOH) Keywords: Rare Disease, Collaborative Networks, Registries
The Amyloidosis and LCH registries aim to improve the quality of patient care and clinical outcomes.
The amyloidosis and the LCH registries were founded at the USZ in 2013 and 2020, respectively. They register, track and monitor patients with these rare entities. The aim is to improve the understanding of the spectrum of these diseases, the patient journies and the barriers health care providers and patients face within the Swiss healthcare system. The registries also serve quality control purposes by allowing comparison of results between different centers. Especially in rare diseases, where there is often a lack of randomized controlled trials, patient registries help to ensure a higher quality of patient care.
Both registries are activities of the swiss LCH and amyloidosis collaborative networks. In these networks, specialists from various USZ disciplines collaborate to improve patient care. Standard operating procedures for the work-up of patients are defined. Regular interdisciplinary board meetings are held in a hybrid format at the USZ. The collaboration and exchange go beyond USZ: both networks work together with other Swiss hospitals and foster the exchange with international centers. In addition, the networks provide education by symposia and educational publications.
Kantonsspital Winterthur Kantonsspital St. Gallen
Universitätsspital Zürich Kantonsspital Baden
Kantonsspital Winterthur
Amyloidosis Registry: Collaborating Centers
Inselspital Bern
EOC Bellinzona
CHUV Lausanne Universitätsspital Basel LCH-Registry
LCH: Langerhanscell-Histiocytosis ECD: Erdheim-Chester-Disease RDD: Rosai-Dorfman-Disease
