Frenzel, Lukas | Hallek, Michael - A 05

In the last few years, the standard of care for CLL has changed from chemotherapy to targeted agents. First-line therapy uses specific inhibitors of BCL2 or Bruton's tyrosine kinase (BTK) in combination with monoclonal antibodies (Ab) against CD202. The elucidation of potential resistance mechanisms to these substances is therefore of great importance.

The key hypothesis of this application is based on the premise that signals of the tumor microenvironment (TME) can modify CLL cells to generate resistance to inhibitor therapy. N New in vivo models with conditional expression of human BCL2 and CD20 in malignant B cell will allow us to study clinically active drugs. We will investigate primary CLL samples upon inhibitor treatment,and we will characterize the composition of TME and CLL cells upon resistance against combination therapies. Moreover, we aim to identify factors in myeloid cells that mediate and support BCL2 inhibitor resistance in CLL cells. Altogether, our overall aim is to investigate the dialogue between CLL cells and the TME as a key mechanism for resistance against novel inhibitor combinations (figure 1).