Fighting Resistance in CLL (FIRE-CLL)

Chronic lymphocytic leukemia (CLL) is a common cancer an its incidence and burden will further increase in our aging Western society. CLL is clinically very diverse, ranging from death within 2-3 years to indolent disease, which is determined by both, the genetic background of the patient but also from the supporting and protecting microenvironment of the cancer cells. One of the clinical relevant questions and challenges is to predict the prognosis of each single patient and to estimate potential therapy success or relapse. In fact all CLL patients relapse sooner or later as none of the currently used standard chemotherapies or novel, targeted and very efficient immunotherapeutics offer long lasting cure. According to very new research results, mutations in distinct cancer genes may be suitable in predicting the course of disease and are also helpful in identifying patients that may become therapy resistant. The analysis of such mutations on a patient-specific basis and the knowledge of how genetic changes in the cancer cell interfere and shape the microenvironment in its tumorsupporting role, is the main topic that will be addressed by FIRE-CLL. Together with leading experts in the field of CLL, both on the clinical and on the scientific site, we aim to fight resistance in CLL by developing tailored therapy concepts which are based on genetic heterogeneity with the aim to turn CLL into a curable disease.

Our data showed that clonal evolution of leukemic cells in mice is extremely dynamic, particularly upon transfer of primary tumors into syngeneic wildtype recipient mice. This plasticity is not only based on the occurrence of novel subclonal somatic mutations but also on a high initial B cell receptor (BCR) specific heterogeneity. This means, that although most of the leukemic cells of a particular CLL case have the same BCR specificity, there are many minor clones with a distinctive BCR profile and hence, also with a distinctive somatic mutation landscape. These minor clones can dramatically expand upon transfer. Thus, interrogating genetic landscapes of TCL1 tumors alongside immune phenotyping in wildtype, immune compromised or genetically modified hosts or in mice subjected to preclinical treatment studies will definitely yield important insight into cancer-immune/microenvironment crosstalk during disease progression and treatment response. The findings from our IRF4 projects are clinically relevant, as immunotherapies were considered as the only treatment option with the potential to cure the disease in the long term, however, strategies to modulate the immune system were less successful in the clinical practice. Treatment of primary CLL patients with Ibrutinib in vivo downregulated genes involved in immune response, including IRF4 and PDL1 in CLL cells as well as PD1 on T-cells. The new findings might explain why Ibrutinib refractory CLL patients did not respond to PD1 treatment in vivo.