Targeting Acute Myeloid Leukemia by the Combination of Expanded Natural Killer Cells and Romidepsin

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1002/pbc.29735

Journal Title

Pediatric Blood and Cancer

Department

Pediatrics

Abstract

Background: Acute myeloid leukemia (AML) accounts for approximately 20-33% of all acute leukemias in children, adolescents and young adults, but is associated with a 50% mortality rate. Leap frog advances with high impact are urgently required to significantly improve outcomes in these high-risk AML patients. Since Natural Killer (NK) cells are an essential component of AML surveillance, and are short- lived when administered ex-vivo, novel combinatorial immunotherapy approaches to clinically enhance NK cell targeting, persistence, and functional activation would significantly enhance AML relapse-free survival. NK therapy has been limited in the past by the low number of active NK in the peripheral blood (PB). Our group has successfully expanded functional and active peripheral blood NK cells (exPBNK) with irradiated feeder cells to target a variety of pediatric cancers (1). Romidepsin is a histone deacetylase inhibitor and it up-regulates the expression of NKG2D ligands such as MICA/B and induces apoptosis in tumor cells (2). Objectives: We aim to investigate if AML cells are sensitive to be killed by ex vivo expanded NK cells and if romidepsin enhances the killing of AML by expanded NK cells. Design/Methods: PBNK cells were ex vivo expanded by co-culturing peripheral blood mononuclear cells with lethally irradiated feeder cells (K562-mbIL21-41BBL) as previously described (3). The in-vitro cytotoxicity of expanded NK against AML cell lines (THP1, HEL and KG1a) were evaluated at different E:T ratios as we have previously described (3). Results: Expanded NK cells expressed high level of NKG2D (99% expression). THP1, HEL and KG1a cells expressed high level of NKG2D ligands MICA/B (99% expression). As expected, THP1, HEL and KG1a cells are sensitive to be killed by the expanded PBNK cells in a E:T ratio dependent manner which may be mediated through the interaction of NKG2D with MICA/B. THP1, HEL and KG1a cells were also sensitive to be killed by romidepsin. Romidepsin did not significantly affect the expression of MICA/B on these tumor cells. But the combination of romidepsin and the expanded NK cells significantly enhanced the killing of THP1, HEL and KG1a cells than expanded NK cells alone (p < .05, p<005, p < .05) or romidepsin alone (p < .05, p < .05, p < .05). Conclusions: Our data demonstrated the anti-tumor efficacy of the combination of romidepsin and expanded NK cells in vitro against AML cells. In the future, we will investigate the vivo anti-AML effect of expanded NK with romidepsin utilizing human AML xenografted immunodeficient mice. Chu/Cairo, Cancer Immunol Res, 2015 Chu/Cairo, Oncoimmunology, 2017 Chu/Cairo, JITC, 2020.

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