Memory-like Natural Killer Cell and CD19 Antibody-Based Immunotherapy in Combination with Tyrosine Kinase Inhibition Has Antitumor Effects against Ph(-like) Acute Lymphoblastic Leukemia.

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a molecularly distinct tyrosine kinase-driven cancer that has a high relapse rate and poor response toward combinatorial chemotherapy. Tyrosine kinase inhibitors (TKI) in the clinic improve the survival of patients with Ph-like ALL. Engineered antibody and cell-based immunotherapies can advance treatment for this genetic subtype of ALL. Allogeneic memory-like natural killer (ML-NK) cells have been used to treat leukemia and have shown a low risk of graft-versus-host reaction, which may be combined with leukemia epitope-targeting antibodies. However, mutation or pathway-directed TKI of Ph-like ALL can interfere with memory function and antibody-dependent NK cell-mediated cytotoxicity (ADCC). In this study, we explored the potential of ML-NK cells and Fc-enhanced CD19-ADCC in combination with TKI directed against kinase-driven leukemia models, including patient-derived xenografted Ph-like ALL. We demonstrate that receptor cross-linking in coculture with K562 feeder cells generated a more robust memory-like state of NK cells than coactivation with soluble IL-12, IL-15, and IL-18, as determined by genomic and functional studies. After receptor cross-linking and subsequent ILs preactivation, the optimized ML-NK cells showed enhanced antileukemic effector functions, which could compensate for exhausted B-cell precursor leukemia-infiltrating primary NK cells. TKI differentially affected multiple features of NK cell biology including viability, expansion, metabolism, receptor repertoire, and cytotoxicity. ADCC was maintained upon exposure to specific Abelson (ABL) or Janus kinase (JAK) inhibitors, in contrast to the multitarget TKI dasatinib impeding spleen tyrosine kinase-dependent ADCC. In conclusion, optimized ML-NK cell and CD19 antibody-based immunotherapy combined with carefully selected TKI demonstrates significant in vitro treatment efficacy in kinase-driven leukemia.