Project Details
Projekt
Optimizing macrophage-mediated responses in antibody-based immunotherapy of ALL
Applicants
Dr. Lennart Lenk; Professor Dr. Denis Schewe
Subject Area
Hematology, Oncology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 444949889
Current treatment protocols achieve high cure rates in children with B-cell precursor (B-) or T-cell (T-) acute lymphoblastic leukemia (ALL). However, these protocols rely on toxic polychemotherapy. Immunotherapy has become a crucial component of ALL treatment, primarily due to the success of CD19-directed therapies. Nevertheless, novel immunotherapeutic approaches are urgently needed, particularly for CD19-negative B-ALL and for T-ALL, where immunotherapy options remain limited. In the first funding period, our working hypothesis was that effective antibody-based immunotherapy for B-ALL could be established by optimizing the recruitment of myeloid effector cells. This can be achieved, for instance, by blocking the myeloid immune checkpoint CD47/SIRPα or by using antibody isotypes, such as IgA, known for their efficient activation of myelocytes. Both strategies—particularly CD47 blockade, which enhances macrophage opsonization—demonstrated promising in vitro and in vivo efficacy in our models. Building on these findings, the second funding period of this project aims to further optimize macrophage effector cell recruitment as a therapeutic strategy in ALL, including T-ALL. We hypothesize that the efficacy of antibodies promoting macrophage phagocytosis can be further enhanced in ALL patients when combined with specific macrophage-activating agents. Additionally, we propose that patient-specific macrophage characteristics, both before and during therapy, influence clinical responses to therapeutic antibody combinations and may serve as biomarkers for treatment outcomes. The results of the proposed experiments will lay the foundation for early clinical trials evaluating the combination of macrophage-activating agents with antibody-based immunotherapy in both pediatric and adult ALL.
DFG Programme
Clinical Research Units
