Center for Molecular Medicine Cologne

Frenzel, Lukas | Hallek, Michael - A 05

The dialogue of CLL cells with the tumor microenvironment as a mediator of treatment resistance against targeted inhibitor combinationslls


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).

Clinical Relevance

CLL is the most common leukemia in the Western world and the majority of patients is still not cured until today. Since survival CLL cells strongly depends on cellular and chemical interactions within its TME, we will investigate the role of specific TME stimuli in mediating resistance to targeted agents such as αCD20Ab/BCL2i/BTKi, which are in current clinical use. Finally, we aim to identify novel treatment options to overcome resistance against combinations of targeted agents.


1) CLL in vivo modelling

2) macrophages

3) BCL2 familiy members

PD Dr. Lukas Frenzel CMMC Cologne
PD Dr. Lukas Frenzel

Clinic I of Internal Medicine

CMMC - PI - A 05

Publications - Lukas Frenzel

Link to PubMed

Affiliations - Lukas Frenzel

CRC 1530

Prof. Dr. Michael Hallek CMMC Cologne
Prof. Dr. Michael Hallek

Clinic I of Internal Medicine

CMMC - Co-PI - A 05

Executive Board Member

Publications - Michael Hallek

Link to PubMed

Affiliations - Michael Hallek

CRC 1530