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. Statement of significance This work represents a potential advancement in the treatment of AML, as it involves the release of IFN-γ by T cells to induce CD38 expression and thus sensitizing leukemia stem cells, which have been resistant to current treatment regimens, to CD38-directed T cell engagers.