Memory-like natural killer cell and CD19-antibody based immunotherapy in combination with tyrosine-kinase inhibition of Ph(-like) acute lymphoblastic leukemia

Abstract

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a molecularly distinct tyrosine kinase-driven entity burdened with a high risk of relapsing disease and poor response toward combinatorial chemotherapy. Tyrosine kinase inhibitors (TKI) have been introduced into recent treatment protocols to improve the survival of patients with Ph-like ALL, yet preliminary data indicate subpar outcome. To advance treatment concepts for this genetic subtype of ALL, engineered antibody and CAR T-cell based immunotherapy has been proposed. Alternatively, the clinical use of natural killer cells endowed with a CAR or combined with leukemia epitope-directed antibodies is a conceivable strategy, which allows for an adoptive transfer of immune cells in an allogeneic setting with a low risk of graft-versus-host reaction. Here, we explored memory-like NK cells and Fc-enhanced CD19 antibody-dependent cell-mediated cytotoxicity (ADCC) in combination with TKI directed against in vitro models of kinase-driven leukemia. We demonstrate that the memory-like state of NK cells is determined by interleukin-mediated epigenetic reprogramming resulting in enhanced antileukemic effector functions. TKI differentially interfere with NK cell function and receptor repertoire, but CD19 antibody-mediated cytotoxicity operates ABL and JAK-independent allowing for simultaneous administration of memory-like NK cells, CD19 antibody, and specific TKI with high treatment efficacy in vitro.