title: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.
abstract: We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
authors.affiliation: Abramson Cancer Center, and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. david.porter@uphs.upenn.edu
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Adam
authors.initials: A
authors.lastname: Bagg
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000361:Agammaglobulinemia / Q000209:etiology; D018941:Antigens, CD19; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D002678:Chimera; D016207:Cytokines / Q000097:blood; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D016086:Lentivirus; D007945:Leukemia, Lymphoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology*; D015275:Tumor Lysis Syndrome / Q000209:etiology
chemical_list: D018941:Antigens, CD19; C000598123:CTL019 chimeric antigen receptor; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell