Article

Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

Stephan A. GruppChildren'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 PhiladelphiaMichael KalosChildren'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 PhiladelphiaDavid M. BarrettChildren'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 PhiladelphiaRichard AplencChildren'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 PhiladelphiaDavid L. PorterChildren'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 PhiladelphiaSusan R. RheingoldChildren'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 PhiladelphiaDavid T. TeacheyChildren'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 PhiladelphiaAnne ChewChildren'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 PhiladelphiaBernd HauckChildren'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 PhiladelphiaJ. Fraser WrightChildren'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 PhiladelphiaMichael C. MiloneChildren'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 PhiladelphiaBruce L. LevineChildren'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 PhiladelphiaCarl H. JuneChildren'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

2013en

ABI

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.

Identifiers

DOI: 10.1056/nejmoa1215134

Citations and references

Cited by 30 references

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