title: Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
abstract: Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: David
authors.initials: D
authors.lastname: Barrett
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rheingold
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Anne
authors.initials: A
authors.lastname: Chew
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hauck
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Milone
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.affiliation: Children's Hospital of Philadelphia (S.A.G., D.B., R.A., S.R.R., D.T.T., B.H., J.F.W.); the Department of Pediatrics (S.A.G., D.B., R.A., S.R.R., D.T.T.), Abramson Cancer Center (S.A.G., M.K., R.A., D.L.P., S.R.R., D.T.T., M.C.M., B.L.L., C.H.J.); and the Departments of Pathology and Laboratory Medicine (M.K., A.C., B.H., J.F.W., M.C.M., B.L.L., C.H.J.) and Medicine (D.L.P.), University of Pennsylvania - all in Philadelphia.
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D018941:Antigens, CD19; D002648:Child; D002678:Chimera; D005260:Female; D006801:Humans; D007167:Immunotherapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018941:Antigens, CD19; D011948:Receptors, Antigen, T-Cell