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

Mariam Murtadha; Miso Park; Yinghui Zhu; Enrico Caserta; Ada Alice Dona; Mahmoud Singer; Hawa Vahed; Theophilus Tasndoh; Asaul Gonzalez; Kevin Ly; James F Sanchez; Arnab Chowdhury; Alex Pozhitkov; Lucy Ghoda; Ling Li; Bin Zhang; Amrita Krishnan; Guido Marcucci; John Williams; Flavia Pichiorri

doi:10.1101/2023.02.27.530273

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

bioRxiv [Preprint]. 2023 Mar 1:2023.02.27.530273. doi: 10.1101/2023.02.27.530273.

Authors

Mariam Murtadha^{1

2}, Miso Park³, Yinghui Zhu^{1

2}, Enrico Caserta^{1

2}, Ada Alice Dona^{1

2}, Mahmoud Singer^{1

2}, Hawa Vahed^{1

2}, Theophilus Tasndoh^{1

2}, Asaul Gonzalez³, Kevin Ly³, James F Sanchez¹, Arnab Chowdhury^{1

4}, Alex Pozhitkov^{1

2}, Lucy Ghoda², Ling Li², Bin Zhang², Amrita Krishnan¹, Guido Marcucci², John Williams³, Flavia Pichiorri^{1

2}

Affiliations

¹ Judy and Bernard Briskin Center for Multiple Myeloma Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope; Duarte, CA, USA.
² Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope; Duarte, CA, USA.
³ Department of Molecular Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA.
⁴ Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope; Duarte, CA, USA.

Abstract

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.

Keywords: CD38; acute myeloid leukemia; bispecific T cell engagers; interferon gamma; leukemia stem cells.

Publication types

Preprint

Grants and funding

R50 CA252135/CA/NCI NIH HHS/United States