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https://hdl.handle.net/2440/54942
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Type: | Journal article |
Title: | Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia |
Author: | Imai, C. Mihara, K. Andreansky, M. Nicholson, I. Pui, C. Geiger, T. Campana, D. |
Citation: | Leukemia, 2004; 18(4):676-684 |
Publisher: | Nature Publishing Group |
Issue Date: | 2004 |
ISSN: | 0887-6924 1476-5551 |
Statement of Responsibility: | C Imai, K Mihara, M Andreansky, I C Nicholson, C-H Pui, T L Geiger and D Campana |
Abstract: | To develop a therapy for drug-resistant B-lineage acute lymphoblastic leukemia (ALL), we transduced T lymphocytes with anti-CD19 chimeric receptors, consisting of an anti-CD19 single-chain variable domain (reactive with most ALL cases), the hinge and transmembrane domains of CD8alpha, and the signaling domain of CD3zeta. We compared the antileukemic activity mediated by a novel receptor ('anti-CD19-BB-zeta') containing the signaling domain of 4-1BB (CD137; a crucial molecule for T-cell antitumor activity) to that of a receptor lacking costimulatory molecules. Retroviral transduction produced efficient and durable receptor expression in human T cells. Lymphocytes expressing anti-CD19-BB-zeta receptors exerted powerful and specific cytotoxicity against ALL cells, which was superior to that of lymphocytes with receptors lacking 4-1BB. Anti-CD19-BB-zeta lymphocytes were remarkably effective in cocultures with bone marrow mesenchymal cells, and against leukemic cells from patients with drug-resistant ALL: as few as 1% anti-CD19-BB-zeta-transduced T cells eliminated most ALL cells within 5 days. These cells also expanded and produced interleukin-2 in response to ALL cells at much higher rates than those of lymphocytes expressing equivalent receptors lacking 4-1BB. We conclude that anti-CD19 chimeric receptors containing 4-1BB are a powerful new tool for T-cell therapy of B-lineage ALL and other CD19+ B-lymphoid malignancies. |
Keywords: | T-cell receptor CD137 acute lymphoblastic leukemia B-cell lymphoma |
DOI: | 10.1038/sj.leu.2403302 |
Published version: | http://dx.doi.org/10.1038/sj.leu.2403302 |
Appears in Collections: | Aurora harvest Paediatrics publications |
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