Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.

TitleChimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Publication TypeJournal Article
Year of Publication2013
AuthorsGrupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, J Wright F, Milone MC, Levine BL, June CH
JournalN Engl J Med
Volume368
Issue16
Pagination1509-18
Date Published2013 Apr 18
ISSN1533-4406
KeywordsAntigens, CD19, Child, Chimera, Female, Humans, Immunotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, T-Cell, Remission Induction, T-Lymphocytes
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.

DOI10.1056/NEJMoa1215134
Alternate JournalN. Engl. J. Med.
PubMed ID23527958
PubMed Central IDPMC4058440
Grant List1R01CA165206 / CA / NCI NIH HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States
R01 CA102646 / CA / NCI NIH HHS / United States
R01 CA116660 / CA / NCI NIH HHS / United States
R01 CA165206 / CA / NCI NIH HHS / United States
R01CA102646 / CA / NCI NIH HHS / United States
R01CA116660 / CA / NCI NIH HHS / United States