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: Stephan A Grupp, Michael Kalos, David Barrett, Richard Aplenc, David L Porter, Susan R Rheingold, David T Teachey, Anne Chew, Bernd Hauck, J Fraser Wright, Michael C Milone, Bruce L Levine, Carl H June
• Journal: The New England journal of medicine (N Engl J Med) Vol. 368 Issue 16 Pg. 1509-1518 (Apr 18 2013) ISSN: 1533-4406 [Electronic] United States
• PMID: 23527958 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD19
• Receptors, Antigen, T-Cell

Topics

• Antigens, CD19
• Child
• Chimera
• Female
• Humans
• Immunotherapy
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (immunology, therapy)
• Receptors, Antigen, T-Cell
• Remission Induction
• T-Lymphocytes (immunology)