T cell receptor gene therapy targeting mutant NPM1 on acute myeloid leukemia
- Other support (specified) The phase I/II clinical trial is sponsored by Miltenyi.
Acute myeloid leukemia (AML) is a life-threatening malignancy that requires further therapeutic improvement. One of the most common AML sub-entities is AML with mutant NPM1 (dNPM1-AML), in which a 4 base pair frameshift insertion occurs in the NPM1 gene. We previously reported on a T cell receptor (TCR) which, upon transfer to CD8 T cells, is able to target AML cells carrying this mutation by recognizing CLAVEEVSL, a 9-mer dNPM1-derived neoantigen presented by HLA-A*02:01. Since dNPM1-AML is a highly heterogeneous disease, highlighted by the recent identification of distinct dNPM1-AML subtypes by bulk transcriptomics, we here investigated the inter- and intra-patient heterogeneity in more detail and assessed the in vitro susceptibility of AML cells with different phenotypes to lysis by dNPM1-A2 TCR-engineered T cells.
A 28-color spectral flow cytometry-based antibody panel was used to phenotype dNPM1-AML cells and to assess lysis of different leukemic cell subsets in co-culture with dNPM1-A2 TCR-T cells.
Different dNPM1-AML cells were identified, with early hematopoietic stem cell- or progenitor-like phenotypes or more mature monocyte- or dendritic cell-like phenotypes. Upon coculture with dNPM1-A2 TCR-engineered T cells, all subpopulations were efficiently lysed, albeit with different kinetics.
The results emphasize the potential of dNPM1-A2 TCR-T cells as a therapeutic strategy to treat patients with dNPM1-AML. This strategy is currently being evaluated in a first-in-human phase I/II clinical trial at the Leiden University Medical Center.