title: Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity.
abstract: Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killingin vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A*02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia. Leukemia escape was not associated with loss of the antigenic target, downregulation of cell surface HLA, antibody pharmacokinetic or biodistribution issues, or development of leukemia cell-intrinsic resistance to ADCC. Interestingly, the rapidity of leukemic growth determined whether leukemia was able to evade cytotoxicity independent of the presence of sufficient effector cells. By engineering leukemia cells with upregulated p27Kip1and slower cell cycling times, we show that relapse was inversely correlated with growth rates resulting in the eventual inadequacy of effector to target ratio. Moreover, lack of migration of effector cells into lymphomatous pockets of ALL also allowed local escape. Successful leukemia therapy with mAb might therefore be improved in similar situations by combination with measures to reduce burden and slow leukemia cell growth.
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, New York, NY, USA; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Dubrovsky
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: Elliott Joseph
authors.initials: EJ
authors.lastname: Brea
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, New York, NY, USA; Immunology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pankov
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute , New York, NY, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Casey
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute , New York, NY, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Dao
authors.affiliation: Eureka Therapeutics , Emeryville, CA, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liu
authors.affiliation: Molecular Pharmacology Program, Sloan-Kettering Institute, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
keywords: ADCC; Leukemia; T-cell receptor mimicking; antibody; escape mechanisms