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Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia

Stephan A. GruppAbramson Cancer Center, University of PennsylvaniaMichael KalosAbramson Cancer Center, University of PennsylvaniaDavid 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 AplencPhiladelphia UniversityDavid L. PorterMedicine, University of PennsylvaniaSusan R. RheingoldAbramson Cancer Center, University of PennsylvaniaDavid T. TeacheyChildren's Hospital of Philadelphia, University of PennsylvaniaAnne 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, University of PennsylvaniaJ. Fraser WrightChildren's Hospital of Philadelphia, University of PennsylvaniaMichael 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. JuneDepartments of Pathology and Laboratory Medicine, University of Pennsylvania

2013en

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Annotatsiya

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.

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DOI: 10.1056/nejmoa1215134

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