Project Details
Projekt
Minimal residual disease characteristics and its immune system interaction in the context of treatment resistance
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Minimal residual disease (MRD) is the most important prognostic factor in acute lymphoblastic leukemia (ALL). Highly sensitive MRD measurement by molecular or flow cytometric methods allows accurate assessment of treatment response and enables prediction of an impending relapse. Most data on MRD kinetics have been collected for ALL patients receiving conventional chemotherapy. Novel treatment approaches as immunotherapies are expanding the treatment landscape in ALL and show fundamentally different MRD and relapse dynamics compared to conventional chemotherapy. However, persistence of MRD defines a group of patients with high risk of relapse irrespective of treatment type. Thus, better understanding mechanisms of MRD persistence under both treatment types is of huge clinical importance.Studies addressing potential resistance mechanisms to different therapeutic regimens are often performed using pretherapeutic leukemia samples. Only few studies focus on residual leukemia under treatment and its crosstalk with the immune system. However, these insights are highly relevant to specifically target and eliminate relapse initiating MRD cells. For example, using mathematical models, we could show that modifying treatment protocols based on the growth rates of residual leukemic cells delayed relapse and eradicated MRD. Besides tumor specific factors, the crosstalk between leukemia and the immune system might play a crucial role in the elimination of residual disease. Leukemic cells may develop mechanisms to escape immune recognition or to suppress the immune system, especially relevant for outcome under immunotherapy. Therefore, our goal within the proposed project is to accurately characterize and compare both MRD cells and the immune system under chemotherapy and immunological approaches in the context of treatment resistance. To this end, we will select samples from MRD good and poor responders under both forms of therapy from the large MRD dataset available in Kiel, and first accurately immunophenotype these samples by multicolor flow cytometry, looking at both leukemia and healthy cells. We will then isolate tumor cells and the different immune cell compartments and study their molecular profiles, in selected cases even at the single cell level. Further, we will validate our results on large patient cohorts by multicolor flow cytometry, also considering the markers that have been identified as relevant in other projects. We hope that these studies will provide detailed understanding of leukemia and host-dependent mechanisms of MRD-persistence under chemo- and immunotherapy and help to delineate factors associated with eradication of MRD. Our analyses will support the development of therapy protocols with optimized sequences and combinations of classical chemotherapy and immunological approaches to eradicate MRD and to improve the chances of cure for ALL patients.
DFG Programme
Clinical Research Units
