Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38^pos), the presence of CD34 and lack of CD38 expression (CD34^posCD38^neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34^posCD38^neg AML blasts, but not in CD34^posCD38^neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38^pos blasts. Activated CD4^pos and CD8^pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34^posCD38^neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38^neg and CD38^pos AML blasts, which culminates in LSC depletion.