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(pos)CD38(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(pos)CD38(neg) AML blasts, but not in CD34(pos)CD38(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(pos)CD38(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.