Project

Preclinical study of TARP-directed cellular and nanobody therapy in pediatric AML: improving survival and quality-of-life

Code
365X09120
Duration
01 November 2020 → 31 October 2024
Funding
Funding by bilateral agreement (private and foundations)
Promotor
Research disciplines
  • Medical and health sciences
    • Cancer therapy
Keywords
pediatric acute myeloid leukemia nanobody TARP
 
Project description

With conventional chemotherapeutic regimens based on anthracycline and cytarabine combinations, high complete remission (CR) rates of more than 90% can be achieved in children diagnosed with acute myeloid leukaemia (AML). Despite these successful response rates, relapse after conventional therapy is common, mainly due to the chemo-refractoriness of leukaemia stem cells (LSCs). While for acute lymphoblastic leukaemia (ALL), several other approaches, like bispecific antibodies and CAR-T-cells targeting CD19, are already in clinical practice, for AML identification of a good target antigen is more difficult. Expression of antigens by AML blasts and LSCs is usually not exclusively restricted to those cells but overlaps with normal haematopoiesis, which results in severe off-tumour haematologic toxicity of antigen-targeting therapies.

We have recently identified an AML-specific target, TARP, that is highly expressed in AML leukaemia blasts and LSCs, and, importantly is absent in virtually all other tissues. As TARP is an intracellular target, presented by MHC-I molecules, we generated TARP-peptide-directed cytotoxic T-cells (CTLs). Our in vitro results showed a specific and efficient killing of AML cells. Interestingly, TARP expression is strongly correlated with FLT3-ITD, a poor prognostic marker. Given these promising results, we wish to further evaluate in vivo efficacy of this TARP-CTL therapy. In addition, we will develop innovative TARP-nanobodies, as an alternative to the CTLs. All required expertise is present in the collaborating research teams in this application. In addition, our team is involved in a recent effort to upgrade the FAGG certified GMP Unit I Cell Therapy in our institution to a FAGG certified Cell and Gene Therapy Unit II, necessary for the production of clinical-grade cell-based therapy.


Moreover, we will also characterize the population of patients that will benefit most from TARP-directed therapy. This will include a comprehensive correlation between TARP expression levels and molecular characteristics e.g. FLT3-ITD and leukaemia characteristics e.g. stem cell load by flow cytometry and treatment response. Finally, to further ensure successful implementation in clinical trials, we will identify RNA-based biomarkers during the course of the project to monitor tumour response and to identify patients benefiting from TARP-directed treatment.