title: Antileukemic potency of CD19-specific T cells against chemoresistant pediatric acute lymphoblastic leukemia.
abstract: Adoptive therapy with chimeric antigen receptor (CAR) T cells (CART cells) has exhibited great promise in clinical trials, with efficient response correlated with CART-cell expansion and persistence. Despite extensive clinical use, the mechanisms regulating CART-cell expansion and persistence have not been completely elucidated. We have examined the antileukemia potency of CART cells targeting CD19 antigen using second-generation CAR containing a CD28 co-stimulatory domain cloned into piggyBac-transposon vector and patient-derived chemoresistant pediatric acute lymphoblastic leukemia samples. In the presence of large numbers of target cells characteristic of patients with high leukemia burden, excessive proliferation of CART cells leads to differentiation into short-lived effector cells. Transient leukemia growth delay was induced by CART-cell infusion in mice xenografted with rapidly growing CD19+ acute lymphoblastic leukemia cells and was followed by rapid CART-cell extinction. Conditioning with the hypomethylating agent 5-aza-2'-deoxycytidine-activating caspase 3 and promotion of apoptosis in leukemia cells maximized the effect of CART cells and improved CART-cell persistence. These data suggest that the clinical use of 5-aza-2'-deoxycytidine before CART cells could be considered. Coculture of leukemia cells with bone marrow stroma cells reduced target cell loss, suggesting that leukemia cell mobilization into circulation may help to remove the protective effect of bone marrow stroma and increase the efficacy of CART-cell therapy.
authors.affiliation: Cord & Marrow Transplant Facility, Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia; Children's Cancer Institute Australia, Sydney, Australia. Electronic address: alla.dolnikov@sesiahs.health.nsw.gov.au.
authors.forename: Alla
authors.initials: A
authors.lastname: Dolnikov
authors.affiliation: Cord & Marrow Transplant Facility, Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia; Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Shen
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, Australia; Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Klamer
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Swapna
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Cord & Marrow Transplant Facility, Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia; Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Micklethwaite
authors.affiliation: Cord & Marrow Transplant Facility, Kids Cancer Centre, Sydney Children's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia; Children's Cancer Institute Australia, Sydney, Australia.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D005260:Female; D064593:Heterografts; D006801:Humans; D016219:Immunotherapy, Adoptive; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D011948:Receptors, Antigen, T-Cell