Mast cells . Mastocytosis . Anaphylaxis . Atopic dermatitis . Angioedema . Tumor microenvironment . Tyrosine kinase inhibitors . Immunotherapies

Allergy and Immunity

 

Our group has a long-standing interest in mast cells and mast cell-related diseases including mastocytosis, anaphylaxis, angioedema and atopic dermatitis. Mastocytosis is a heterogenous disease characterized by clonal expansion of mast cells in multiple organs, particularly the bone marrow and skin. Clinical manifestation includes mast cell mediator symptoms such as anaphylaxis as well as dysfunction of various organ systems such as cytopenia, hepatosplenomegaly, and malabsorption. The most common molecular alteration is an activating mutation in the KIT gene, KITD816V, carried by more than 90% of patients. Additional oncogenic mutations are typically found in patients with advanced disease categories like mast cell leukemia, most commonly in the genes TET2, SRSF2, ASXL1 and JAK2. The course of the disease ranges from chronic in non-advanced categories to progressive in advanced categories. Current treatment options include antihistamines, omalizumab, and new KIT-targeting tyrosine kinase inhibitors (TKI) like midostaurin and avapritinib, but are often not sufficient to control symptoms.

At the University Hospital Basel we see mastocytosis patients from all over Switzerland in the Interdisciplinary Mastocytosis Clinic. The Mastocytosis Clinic is one of the few centres worldwide that participates in clinical trials investigating several new compounds such as the KIT-targeting TKIs avapritinib and BLU-263. We are currently establishing and maintaining a clinical database and a biobank of patients with mastocytosis. Furthermore, patients seen in the Mastocytosis Clinic are enrolled in the international patient registry of the European Competence Network on Mastocytosis (ECNM) after informed consent.

During the past years, we were able to identify novel biomarkers and therapeutic targets, we detected new KIT mutations in familial mastocytosis, developed new classifications and diagnostic criteria and initiated and conducted clinical trials in mastocytosis. We also generated novel Cre-transgenic mouse models with conditional expression of KIT for research on mastocytosis and mast cells.

 

Currently, we pursue three main research lines:

1) Establishment and characterization of good pre-clinical mouse models for mastocytosis

We use mouse models based on the Cre-loxP system for research on mast cells. These mice are analyzed for disease development using multiple methods (blood counts, flow cytometry, ELISA, immohistochemistry), and typical mastocytosis symptoms (mast cell accumulation and proliferation, altered blood counts, anaphylaxis) are evaluated. 

 

2) Characterization of the mastocytosis tumor microenvironment

Tumor phenotypes, both in solid tumors as well as in hematologic neoplasms, are not only dictated by the neoplastic cells themselves, but also by the tumor microenvironment, which has come more and more into focus in recent years as a critical component for the pathogenesis of the disease as well as for the identification of novel therapeutic targets. Immunotherapies, bispecific antibodies, and immune checkpoint inhibitors targeting their respective receptors have emerged as promising therapeutic options in multiple hematologic malignancies. Some of these novel immunotherapies are also explored in combination with TKIs or other targeted drugs, which focus on direct inhibition of activated signaling pathways in the neoplastic cells. Since the tumor microenvironment in mastocytosis has hardly been studied to date, we aim to investigate its composition and function by using RNA-sequencing, multicolor flow cytometry, CyTOF and immunohistochemistry approaches.

 

3) Identification of novel biomarkers and therapeutic options for mastocytosis

Although new ways of treatment for mastocytosis have been developed recently, the vast majority of patients are still not treated sufficiently. Development of new therapeutic compounds in mastocytosis is generally slow with only few clinical trials available to date. Therefore, identifying novel therapeutic strategies with high efficacy, used alone or in combination with KIT-targeting tyrosine kinase inhibitors, will greatly improve the treatment of patients with mastocytosis.

We use (multiplexed) immunoassays on patient samples collected in the Mastocytosis Clinic to identify novel biomarkers in mastocytosis with the aim of developing targeted treatment strategies. These biomarkers are then analyzed in serum and tissue samples of patients and in mastocytosis cell lines. Treatment studies will then be performed using patient material, mast cell lines as well as murine models of mastocytosis.