Inhibitors support immunotherapy for Leukemia

Reiter K, Polzer H, Krupka C, Maiser A, Vick B, Rothenberg-Thurley M, Metzeler KH, Dörfel D, Salih HR, Jung G, Nößner E, Jeremias I, Hiddemann W, Leonhardt H, Spiekermann K, Subklewe M, Greif PA. Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia. Leukemia (2017) 1-10. doi: 10.1038/leu.2017.257.

See the recent press release from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ).

Cited from abstract:
The fms-related tyrosine kinase 3 (FLT3) receptor has been extensively studied over the past two decades with regards to oncogenic alterations that do not only serve as prognostic markers but also as therapeutic targets in acute myeloid leukemia (AML). Internal tandem duplications (ITDs) became of special interest in this setting as they are associated with unfavorable prognosis. Due to sequence52 dependent protein conformational changes FLT3-ITD tends to auto-phosphorylate and displays a
constitutive intracellular localization. Here, we analyzed the effect of tyrosine kinase inhibitors (TKIs) on the localization of the FLT3 receptor and its mutants. TKI-treatment increased the surface expression through upregulation of FLT3 and glycosylation of FLT3-ITD and FLT3-D835Y mutants. In T cell-mediated cytotoxicity (TCMC) assays, using a bispecific FLT3xCD3 antibody construct, the combination with TKI-treatment increased T cell-mediated cytotoxicity of the FLT3-ITD-positive AML cell lines MOLM-13 and MV4-11, patient derived xenograft cells and primary patient samples. Our findings provide the basis for a rational combination of TKI and FLT3-directed immunotherapy with potential benefit for FLT3-ITD-positive AML patients.