CAR T Cell Therapies for Pediatric Solid Tumors
MSc Andrea Timpanaro: PhD student
Prof. Dr. med Jochen Rössler: project co-supervisor
PD Dr. Michele Bernasconi: project supervisor

CAR T cells are engineered T cells expressing chimeric antigen receptors (CARs). CARs are fusion proteins composed by an extracellular antigen binding moiety recognizing tumor surface antigens, a transmembrane domain, and intracellular effector domains.

CAR T cells therapy is one of the most promising approaches against relapsed or otherwise untreatable cancer. Since 2018, our laboratory focuses on this personalized immunotherapy, in order to enhance the normal capacity of the patient's immune system to recognize and attack the tumor. Investigation of surfaceome in solid tumors allows the selection of specific targets. We have investigated rhabdomyosarcoma surfaceome in order to identify optimal targets for CAR T cells. We are now conducting in vitro and in vivo experiments to armor CAR T lymphocytes and test new drugs.

Cooperation with: Prof. Scott McComb, Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Canada: Prof. Dr. med Robbie Majzner, Pediatric Hematology and Oncology, the Stanford University Medical Center, CA.

Disease-targeted next generation sequencing panel (VASCSequ) for detection of somatic-mosaic mutations in congenital vascular malformations to enable further advances in personalized therapeutic decision making
We aim to explore the applicability of disease-targeted next generation sequencing (NGS) for testing of multiple somatic mosaic mutations in patients with congenital vascular malformation (CVM)

• Customized disease-targeted gene panel (“VASCSeq”) sequencing designed to target 14 known
  malformation genes with mutational hot spots published in the literature

• Consolidate an interdisciplinary collaboration network of vascular physicians, pediatricians, radiologists
  and geneticists to enable knowledge exchange and consistent project implementation between Bern
  and Brussel

• Develop standardized imaging and image analysis protocols to allow use of new imaging biomarkers
  to support a truly multiscale trial design.

Cooperation partners: Prof. Iris Baumgartner, Angiology; Prof. Hendrik von Tengg-Kobligk, Radiology, Prof. Miikka Vikkula, Genetics (Brussels, Belgium)

Funding: SNF – SYNERGIA

HERMES: In patients with hemophilia A and B (PWH), the availability of clotting factor concentrates and the introduction of prophylactic home treatment in developed countries greatly improved clinical outcomes. As the life expectancy of PWH has increased, the management of comorbidities has become an area of greater focus within the hemophilia comprehensive care setting. Although most studies focused on somatic problems and complications, a small but growing body of work reports increased prevalence of mental health problems in PWH. To date, very little is known on factors that influence mental ill-health of PWH. The aim of this project is to pilot a Switzerland-based, multicentre, cross-sectional study that is designed to assess the relationship between hemophilia and comorbid mental health problems (including quality of life and psychosocial functioning) in different age groups using psychiatric interviews and psychological questionnaires, and investigate whether age moderates this relationship.

This pilot study will show feasibility and meaningfulness of research on mental ill-health in hemophilia and will set the ground for a larger, multicentre project.

Cooperating partners: Prof. Dr. Johanna Kremer Hovinga, Department of Hematology, Inselspital Bern; Prof. Dr. Michael Kaess, PD Dr. Julian Koenig, Stefan Lerch, University Hospital for Child and Adolescent Psychiatry and Psychotherapy, UPD Bern

Influence of specific cancer therapies and chronic disease on emotions and mental health
MSc Sabine Nafzger, PhD student
Dr. med. Martina De Gaudenzi, postdoctoral researcher
Dr. med. Mutlu Kartal-Kaess, principal investigator

EMOKid: Glucocorticoids (GC) in supranormal dosing play an important role in the treatment regimens of pediatric patients with acute lymphoblastic leukemia (ALL), Hodgkin`s disease (HD) and Non-Hodgkin lymphoma (NHL). Since their introduction in the 1950s, GC have been associated with emotional dysregulation (EDR), ranging from psychotic symptoms to mild changes in mood and cognition, in addition to their well-known physical side effects. The majority of research on EDR associated with GC treatment has been in adult populations, while only a number of controlled prospective trials in children and adolescents provide preliminary findings on GC associated EDR. In particular, it has been difficult to disentangle EDR caused by GC from "normal" responses to stress and anxiety provoked by the underlying illness for which GC are prescribed.

In this study named "EMOKid", we are prospectively analysing EDR due to GC therapy in children with hematological malignancies, mainly ALL, NHL and HD. We aim to address individual variation within patients by standardized assessment of GC effects on emotional states and reactions, neurocognitive functioning (such as emotion recognition, -inhibition and memory), health-related quality of life (HRQoL) as well as psychophysiological and neuroendocrine activity during a GC treatment phase compared to a GC free interval (within-subject).

Cooperatiion with: Prof. Dr. Michael Kaess, PD Dr. Julian Koenig, Stefan Lerch, University Hospital for Child and Adolescent Psychiatry and Psychotherapy, UPD Bern

Late Effects in adult Survivors of Childhood Cancer: Needs, Evaluation of interdisciplinary Clinic
Dr. med. Eva Maria Tinner: PI
Prof. Dr. med Jochen Rössler: Co-PI
Prof. Dr. med. Dr. phil. Maria Wertli: Co-PI

Survivors of Childhood Cancer suffer from late effects caused by their disease and the aggressive treatment they received. The frequency and severity of these late effects augment with age and can affect all organs. Compared with peers who have not had cancer morbidity and mortality is elevated in Childhood Cancer Survivors. We run specific interdisciplinary late effects clinics in Liestal and at the University Hospital Bern Inselspital, in which adults are being seen according to evidence based guidelines (COG-LTFU-Guidelines) by Internal Medicine doctors in cooperation with pediatric oncologists. We also empower the patients by informing them thoroughly about the disease and treatment they had using the tool Passport for Care®. Since the way we conduct these clinics is new, we accompany the clinics with a research project to measure the impact we have on the quality of life of our patients, if we satisfy the needs of our patients, and observe their current health problems.

Cooperation with: Prof. Jörg Leuppi, head of internal medicine Kantonsspital Baselland Liestal, Prof. Gisela Michel, Professor of Health and Social Behavior Director MSc Health Sciences Lucerne, Prof. Claudia Kühni, Head of Research Group, Institute of Social and Preventive Medicine (ISPM)

Mechanisms of genomic instability in childhood cancer

Dr. med. Mutlu Kartal-Kaess, principal investigator
Prof. Dr. med. Jochen Rössler, co-investigator
Clonal Hematopoiesis of indeterminate Potential (CHIP):

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in peripheral blood mononuclear cells of otherwise healthy adults that has been associated with increased risk of developing hematological malignancies. Given the nature of CHIP being an age-related condition, it remains unclear how, in children and adolescents, cellular stressors, such as cytotoxic therapy, influence the expansion of clones carrying mutations in genes commonly affected in CHIP (e.g. DNA damage response genes). The incidence of clonal hematopoiesis after chemotherapy in children and adolescents has not been thoroughly investigated yet.

High-dose chemotherapy followed by reinfusion of autologous stem cells is a substantial part of the standard treatment in solid tumors such as neuroblastomas, gliomas and Ewing sarcomas in children and adolescents. As part of the largest Swiss stem cell program located at the University Hospital of Bern, our Department of Pediatric Hematology and Oncology has a longstanding experience in performing high-dose chemotherapies and autologous stem cell reinfusions for the majority of pediatric patients in Switzerland. Within this program, we investigate samples routinely collected and stored after stem cell harvest to characterize clonal hematopoiesis in children after cytotoxic therapy.

We are aiming to investigate whether the stress from cytotoxic therapy promotes the expansion of CHIP clones and its association with clinical parameters.

Cooperating partners: Prof. Dr. Vera Ulrike Bacher, Dr. Naomi Porret, Core Genomic Facility, Inselspital Bern; Prof. Dr. Gabriela Baerlocher, Stem Cell Laboratory, Inselspital Bern

Our aim is to improve existing therapies for pediatric solid tumors and to devise novel therapies, with a particular focus on rhabdomyosarcoma.

The treatment of tumors in children must meet specific needs, as chemotherapeutic agents can lead to significant long-term consequences. It is therefore the aim of our research to optimize existing therapies by targeting them to the tumor, sparing normal tissues and minimizing long-term side effects.

In a friendly and enthusiastic atmosphere, we can also count on collaborations with the DBMR Mass Spectrometry, Flow Cytometry, Life Cell Imaging and Animal Facilities.

Master work projects: if you are interested in performing a master work in one of our projects, please contact michele.bernasconi@STOP-SPAM.dbmr.unibe.ch

Please visit our Lab Website for more information.

Targeted Nanomedicine
MSc Dzhangar Dzhumashev: PhD student
PD Dr. Michele Bernasconi: project co-supervisor
Prof. Dr. med Jochen Rössler: project supervisor

One strategy we are following is targeted drug delivery by drug-loaded nanoparticles decorated with cancer-specific ligands that promote tumor accumulation and decrease toxicity for patients. We are developing approaches based on two well established technologies: lipid nanoparticles (liposomes) and silica nanotubes.
Liposomes are small lipid vesicles, approximately 100 nm in size.
Silica nanotubes are hollow tubes, 30 to 300 nm in length, with an inner diameter of 10-20 nm.
Both liposomes and silica nanotubes can be loaded with chemotherapeutic agents. We collaborate with the group of Prof. Jean-Olivier Durand at the Institut Charles Gerhardt in Montpellier, who is an expert in mesoporous silica nanoparticles.

We have performed a fluorescent-based screening of peptides and nanobody ligands to target the most common pediatric soft tissue sarcoma, rhabdomyosarcoma.

We have optimized the technology to decorate nanoparticles with these molecules. The most effective nanoparticle design will be selected to achieve enhanced delivery of cytotoxic compounds in pre-clinical models.

Cooperation with: Prof. Paola Luciani, Departement für Chemie und Biochemie, Universität Bern; Dr. Frédérique Cunin, Dr. Jean-Olivier Durand Institut Charles Gerhardt Montpellier, Université de Montpellier, France; Dr. Institut des Biomolécules Max Mousseron, Faculté de Pharmacie, Université de Montpellier, France; Dr. Franck Perez, Dr. Sandrine Moutel, Institut Curie, Paris, France.

The Role of Centrosomes in High Hyperdiploid Acute Lymphoblastic Leukemia

Pediatric acute lymphoblastic leukemia (pALL) is the most common childhood malignancy, accounting for 80% of all leukemias among children aged 0-14 years. Cure rates have enhanced notably in the past decades, still pALL remains to be the leading cause of cancer-related deaths in children. About 75% of all pALL cases show recurring chromosomal alterations, 25-30% having an elevated chromosome number of 51-67, a state termed high-hyperdiploidy (HHD). The underlying pathomechanism behind this phenomenon is still poorly understood. Sequential chromosomal gains and chromosomal instability are critical features in HHD-pALL evolvement and the most common cause of chromosomal instability is centrosome amplification. Although the causal relationship between centrosome amplification and cancer is still not clear, recent findings indicate that inhibiting centrosome clustering (mechanism by which tumor cells control centrosome amplification to retain viability) is a promising therapeutic avenue.

Opposed to most solid and hematological malignancies, the role of centrosome amplification in HHD-pALL has not been clarified so far. Primary goal of this project is to clarify the role of centrosome (patho)biology and the genetic characteristics in HHD-pALL.

Cooperating partners: Prof. Dr. Alwin Krämer, Dr. Gabor Pajor, Clinical Cooperation Unit Molecular Oncology, German Cancer Research Center, Heidelberg, Deutschland; Prof. Dr. Jean-Pierre Bourquin, Universitäts-Kinderspital Zürich