Preclinical evaluation of newly identified therapeutic targets in pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) is a rare disease in pediatrics and the diagnosis is made in 10-15 patients per year in Belgium. Although the overall survival is improved in the previous decades, survival rates are currently not exceeding 60-70% despite intensive chemotherapy regimens and for some children also stem cell transplantation. The recent success of chimeric antigen receptor (CAR) T-cel therapy directed towards CD19 and the CD19-Bispecific T-cell Engager (BiTE) Blinatumomab in the treatment of B-cell acute lymphoblastic leukemia (ALL) has demonstrated the feasibility of applying immunotherapies in childhood cancer, but also highlighted some of the pitfalls that may be encountered in its early phase development. The fundamental biological factor limiting the extension of immunotherapy for the treatment of AML is the lack of a leukemia-specific antigen, or an antigen shared by haematopoietic stem and progenitor cells whose sustained depletion could be clinically tolerated.

Within the framework of a successful previous research project (2016-2020, FWO fellowship Barbara Depreter) we obtained a global picture of the transcriptome characterizing pediatric AML, and specifically, leukemic stem cells (LSCs). We identified TARP to be highly expressed in leukemic cells, including therapy resistant LSCs, of a subgroup of patients, while absent in normal counterparts (Depreter et al., 2019; Depreter et al. 2020).

TARP expression is only found in a subset of pediatric AML (FLT3-ITD AML; +/- 15% of all cases) which will limit its clinical applicability, and translation to clinical studies will be hampered by competing phase 2-3 trials using FLT3-inhibitors in the same patient cohorts. Therefore, we will focus on other prime candidate immunotargets (EMP1 and ANXA2) that were already identified in the above-mentioned research project evaluating the transcriptome of pediatric AML disease. In the current project, we wish to use the experiences gained through TARP evaluation to further investigate the potential of these additional targets. This will contribute to development of a broader arsenal of novel therapeutic options for relapsed pediatric AML. The feasibility and progress of this project will benefit strongly from the experimental pipeline in place, and hurdles already taken in the TARP project.